Checkpoint Kinase 2: Enzyme activated in response to DNA DAMAGE involved in cell cycle arrest. The gene is located on the long (q) arm of chromosome 22 at position 12.1. In humans it is encoded by the CHEK2 gene.Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.Cell Cycle Proteins: Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.DNA Damage: Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.Ataxia Telangiectasia Mutated Proteins: A group of PROTEIN-SERINE-THREONINE KINASES which activate critical signaling cascades in double strand breaks, APOPTOSIS, and GENOTOXIC STRESS such as ionizing ultraviolet A light, thereby acting as a DNA damage sensor. These proteins play a role in a wide range of signaling mechanisms in cell cycle control.Genes, cdc: Genes that code for proteins that regulate the CELL DIVISION CYCLE. These genes form a regulatory network that culminates in the onset of MITOSIS by activating the p34cdc2 protein (PROTEIN P34CDC2).G2 Phase: The period of the CELL CYCLE following DNA synthesis (S PHASE) and preceding M PHASE (cell division phase). The CHROMOSOMES are tetraploid in this point.M Phase Cell Cycle Checkpoints: The cellular signaling system that halts the progression of cells through MITOSIS or MEIOSIS if a defect that will affect CHROMOSOME SEGREGATION is detected.Mitosis: A type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species.Cell Cycle: The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Cell Cycle Checkpoints: Regulatory signaling systems that control the progression through the CELL CYCLE. They ensure that the cell has completed, in the correct order and without mistakes, all the processes required to replicate the GENOME and CYTOPLASM, and divide them equally between two daughter cells. If cells sense they have not completed these processes or that the environment does not have the nutrients and growth hormones in place to proceed, then the cells are restrained (or "arrested") until the processes are completed and growth conditions are suitable.S Phase: Phase of the CELL CYCLE following G1 and preceding G2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome.Protein Kinase Inhibitors: Agents that inhibit PROTEIN KINASES.cdc25 Phosphatases: A subclass of dual specificity phosphatases that play a role in the progression of the CELL CYCLE. They dephosphorylate and activate CYCLIN-DEPENDENT KINASES.Phosphatidylinositol 3-Kinases: Phosphotransferases that catalyzes the conversion of 1-phosphatidylinositol to 1-phosphatidylinositol 3-phosphate. Many members of this enzyme class are involved in RECEPTOR MEDIATED SIGNAL TRANSDUCTION and regulation of vesicular transport with the cell. Phosphatidylinositol 3-Kinases have been classified both according to their substrate specificity and their mode of action within the cell.DNA Replication: The process by which a DNA molecule is duplicated.Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase.Saccharomyces cerevisiae Proteins: Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.CDC2 Protein Kinase: Phosphoprotein with protein kinase activity that functions in the G2/M phase transition of the CELL CYCLE. It is the catalytic subunit of the MATURATION-PROMOTING FACTOR and complexes with both CYCLIN A and CYCLIN B in mammalian cells. The maximal activity of cyclin-dependent kinase 1 is achieved when it is fully dephosphorylated.Spindle Apparatus: A microtubule structure that forms during CELL DIVISION. It consists of two SPINDLE POLES, and sets of MICROTUBULES that may include the astral microtubules, the polar microtubules, and the kinetochore microtubules.MAP Kinase Signaling System: An intracellular signaling system involving the MAP kinase cascades (three-membered protein kinase cascades). Various upstream activators, which act in response to extracellular stimuli, trigger the cascades by activating the first member of a cascade, MAP KINASE KINASE KINASES; (MAPKKKs). Activated MAPKKKs phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES which in turn phosphorylate the MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs). The MAPKs then act on various downstream targets to affect gene expression. In mammals, there are several distinct MAP kinase pathways including the ERK (extracellular signal-regulated kinase) pathway, the SAPK/JNK (stress-activated protein kinase/c-jun kinase) pathway, and the p38 kinase pathway. There is some sharing of components among the pathways depending on which stimulus originates activation of the cascade.Schizosaccharomyces pombe Proteins: Proteins obtained from the species Schizosaccharomyces pombe. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.Schizosaccharomyces: A genus of ascomycetous fungi of the family Schizosaccharomycetaceae, order Schizosaccharomycetales.G2 Phase Cell Cycle Checkpoints: CELL CYCLE regulatory signaling systems that are triggered by DNA DAMAGE or lack of nutrients during G2 PHASE. When triggered they restrain cells transitioning from G2 phase to M PHASE.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.Intracellular Signaling Peptides and Proteins: Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.S Phase Cell Cycle Checkpoints: Cell regulatory signaling system that controls progression through S PHASE and stabilizes the replication forks during conditions that could affect the fidelity of DNA REPLICATION, such as DNA DAMAGE or depletion of nucleotide pools.Kinetochores: Large multiprotein complexes that bind the centromeres of the chromosomes to the microtubules of the mitotic spindle during metaphase in the cell cycle.Tumor Suppressor Proteins: Proteins that are normally involved in holding cellular growth in check. Deficiencies or abnormalities in these proteins may lead to unregulated cell growth and tumor development.Saccharomyces cerevisiae: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.DNA Repair: The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.Calcium-Calmodulin-Dependent Protein Kinases: A CALMODULIN-dependent enzyme that catalyzes the phosphorylation of proteins. This enzyme is also sometimes dependent on CALCIUM. A wide range of proteins can act as acceptor, including VIMENTIN; SYNAPSINS; GLYCOGEN SYNTHASE; MYOSIN LIGHT CHAINS; and the MICROTUBULE-ASSOCIATED PROTEINS. (From Enzyme Nomenclature, 1992, p277)Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Protein-Tyrosine Kinases: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.Cell Line, Tumor: A cell line derived from cultured tumor cells.src-Family Kinases: A PROTEIN-TYROSINE KINASE family that was originally identified by homology to the Rous sarcoma virus ONCOGENE PROTEIN PP60(V-SRC). They interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways. Oncogenic forms of src-family kinases can occur through altered regulation or expression of the endogenous protein and by virally encoded src (v-src) genes.Nocodazole: Nocodazole is an antineoplastic agent which exerts its effect by depolymerizing microtubules.HeLa Cells: The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.Radiation, Ionizing: ELECTROMAGNETIC RADIATION or particle radiation (high energy ELEMENTARY PARTICLES) capable of directly or indirectly producing IONS in its passage through matter. The wavelengths of ionizing electromagnetic radiation are equal to or smaller than those of short (far) ultraviolet radiation and include gamma and X-rays.Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.Tumor Suppressor Protein p53: Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.Cdc20 Proteins: Highly conserved proteins that specifically bind to and activate the anaphase-promoting complex-cyclosome, promoting ubiquitination and proteolysis of cell-cycle-regulatory proteins. Cdc20 is essential for anaphase-promoting complex activity, initiation of anaphase, and cyclin proteolysis during mitosis.Methyl Methanesulfonate: An alkylating agent in cancer therapy that may also act as a mutagen by interfering with and causing damage to DNA.Protein Kinase C: An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters.p38 Mitogen-Activated Protein Kinases: A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.DNA Breaks, Double-Stranded: Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.Aurora Kinases: A family of highly conserved serine-threonine kinases that are involved in the regulation of MITOSIS. They are involved in many aspects of cell division, including centrosome duplication, SPINDLE APPARATUS formation, chromosome alignment, attachment to the spindle, checkpoint activation, and CYTOKINESIS.G1 Phase: The period of the CELL CYCLE preceding DNA REPLICATION in S PHASE. Subphases of G1 include "competence" (to respond to growth factors), G1a (entry into G1), G1b (progression), and G1c (assembly). Progression through the G1 subphases is effected by limiting growth factors, nutrients, or inhibitors.RNA, Small Interfering: Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.Cyclic AMP-Dependent Protein Kinases: A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Fungal Proteins: Proteins found in any species of fungus.Ultraviolet Rays: That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-UV or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-UV or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Cyclin B: A cyclin subtype that is transported into the CELL NUCLEUS at the end of the G2 PHASE. It stimulates the G2/M phase transition by activating CDC2 PROTEIN KINASE.Mitogen-Activated Protein Kinase 1: A proline-directed serine/threonine protein kinase which mediates signal transduction from the cell surface to the nucleus. Activation of the enzyme by phosphorylation leads to its translocation into the nucleus where it acts upon specific transcription factors. p40 MAPK and p41 MAPK are isoforms.Chromosome Segregation: The orderly segregation of CHROMOSOMES during MEIOSIS or MITOSIS.DNA, Fungal: Deoxyribonucleic acid that makes up the genetic material of fungi.Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each.Genomic Instability: An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Mitogen-Activated Protein Kinase Kinases: A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES and are themselves phosphorylated by MAP KINASE KINASE KINASES. JNK kinases (also known as SAPK kinases) are a subfamily.Protein Structure, Tertiary: The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.JNK Mitogen-Activated Protein Kinases: A subgroup of mitogen-activated protein kinases that activate TRANSCRIPTION FACTOR AP-1 via the phosphorylation of C-JUN PROTEINS. They are components of intracellular signaling pathways that regulate CELL PROLIFERATION; APOPTOSIS; and CELL DIFFERENTIATION.p21-Activated Kinases: A family of serine-threonine kinases that bind to and are activated by MONOMERIC GTP-BINDING PROTEINS such as RAC GTP-BINDING PROTEINS and CDC42 GTP-BINDING PROTEIN. They are intracellular signaling kinases that play a role the regulation of cytoskeletal organization.RNA Interference: A gene silencing phenomenon whereby specific dsRNAs (RNA, DOUBLE-STRANDED) trigger the degradation of homologous mRNA (RNA, MESSENGER). The specific dsRNAs are processed into SMALL INTERFERING RNA (siRNA) which serves as a guide for cleavage of the homologous mRNA in the RNA-INDUCED SILENCING COMPLEX. DNA METHYLATION may also be triggered during this process.Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.Mitogen-Activated Protein Kinase 3: A 44-kDa extracellular signal-regulated MAP kinase that may play a role the initiation and regulation of MEIOSIS; MITOSIS; and postmitotic functions in differentiated cells. It phosphorylates a number of TRANSCRIPTION FACTORS; and MICROTUBULE-ASSOCIATED PROTEINS.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.Gamma Rays: Penetrating, high-energy electromagnetic radiation emitted from atomic nuclei during NUCLEAR DECAY. The range of wavelengths of emitted radiation is between 0.1 - 100 pm which overlaps the shorter, more energetic hard X-RAYS wavelengths. The distinction between gamma rays and X-rays is based on their radiation source.Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.Staurosporine: An indolocarbazole that is a potent PROTEIN KINASE C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)Replication Protein A: A single-stranded DNA-binding protein that is found in EUKARYOTIC CELLS. It is required for DNA REPLICATION; DNA REPAIR; and GENETIC RECOMBINATION.MAP Kinase Kinase Kinases: Mitogen-activated protein kinase kinase kinases (MAPKKKs) are serine-threonine protein kinases that initiate protein kinase signaling cascades. They phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES; (MAPKKs) which in turn phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs).Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.Creatine Kinase: A transferase that catalyzes formation of PHOSPHOCREATINE from ATP + CREATINE. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic ISOENZYMES have been identified in human tissues: the MM type from SKELETAL MUSCLE, the MB type from myocardial tissue and the BB type from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.Casein Kinase II: A ubiquitous casein kinase that is comprised of two distinct catalytic subunits and dimeric regulatory subunit. Casein kinase II has been shown to phosphorylate a large number of substrates, many of which are proteins involved in the regulation of gene expression.Cell Nucleus: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)Meiosis: A type of CELL NUCLEUS division, occurring during maturation of the GERM CELLS. Two successive cell nucleus divisions following a single chromosome duplication (S PHASE) result in daughter cells with half the number of CHROMOSOMES as the parent cells.CDC2-CDC28 Kinases: A family of cell cycle-dependent kinases that are related in structure to CDC28 PROTEIN KINASE; S CEREVISIAE; and the CDC2 PROTEIN KINASE found in mammalian species.Chromosomal Proteins, Non-Histone: Nucleoproteins, which in contrast to HISTONES, are acid insoluble. They are involved in chromosomal functions; e.g. they bind selectively to DNA, stimulate transcription resulting in tissue-specific RNA synthesis and undergo specific changes in response to various hormones or phytomitogens.MAP Kinase Kinase 1: An abundant 43-kDa mitogen-activated protein kinase kinase subtype with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.eIF-2 Kinase: A dsRNA-activated cAMP-independent protein serine/threonine kinase that is induced by interferon. In the presence of dsRNA and ATP, the kinase autophosphorylates on several serine and threonine residues. The phosphorylated enzyme catalyzes the phosphorylation of the alpha subunit of EUKARYOTIC INITIATION FACTOR-2, leading to the inhibition of protein synthesis.PhosphoproteinsImmunoblotting: Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.Gene Expression Regulation, Fungal: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in fungi.Casein Kinases: A group of protein-serine-threonine kinases that was originally identified as being responsible for the PHOSPHORYLATION of CASEINS. They are ubiquitous enzymes that have a preference for acidic proteins. Casein kinases play a role in SIGNAL TRANSDUCTION by phosphorylating a variety of regulatory cytoplasmic and regulatory nuclear proteins.Recombinant Fusion Proteins: Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.Phosphoserine: The phosphoric acid ester of serine.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40.Ribosomal Protein S6 Kinases: A family of protein serine/threonine kinases which act as intracellular signalling intermediates. Ribosomal protein S6 kinases are activated through phosphorylation in response to a variety of HORMONES and INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS. Phosphorylation of RIBOSOMAL PROTEIN S6 by enzymes in this class results in increased expression of 5' top MRNAs. Although specific for RIBOSOMAL PROTEIN S6 members of this class of kinases can act on a number of substrates within the cell. The immunosuppressant SIROLIMUS inhibits the activation of ribosomal protein S6 kinases.Anaphase: The phase of cell nucleus division following METAPHASE, in which the CHROMATIDS separate and migrate to opposite poles of the spindle.Nucleic Acid Synthesis Inhibitors: Compounds that inhibit cell production of DNA or RNA.DNA-Activated Protein Kinase: A serine-threonine protein kinase that, when activated by DNA, phosphorylates several DNA-binding protein substrates including the TUMOR SUPPRESSOR PROTEIN P53 and a variety of TRANSCRIPTION FACTORS.Aurora Kinase B: An aurora kinase that is a component of the chromosomal passenger protein complex and is involved in the regulation of MITOSIS. It mediates proper CHROMOSOME SEGREGATION and contractile ring function during CYTOKINESIS.HCT116 Cells: Human COLORECTAL CARCINOMA cell line.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.DNA Helicases: Proteins that catalyze the unwinding of duplex DNA during replication by binding cooperatively to single-stranded regions of DNA or to short regions of duplex DNA that are undergoing transient opening. In addition DNA helicases are DNA-dependent ATPases that harness the free energy of ATP hydrolysis to translocate DNA strands.Cyclin-Dependent Kinase Inhibitor p21: A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.DNA: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).Adaptor Proteins, Signal Transducing: A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymesRecombinant Proteins: Proteins prepared by recombinant DNA technology.Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.Cell Proliferation: All of the processes involved in increasing CELL NUMBER including CELL DIVISION.Extracellular Signal-Regulated MAP Kinases: A mitogen-activated protein kinase subfamily that is widely expressed and plays a role in regulation of MEIOSIS; MITOSIS; and post mitotic functions in differentiated cells. The extracellular signal regulated MAP kinases are regulated by a broad variety of CELL SURFACE RECEPTORS and can be activated by certain CARCINOGENS.ThiophenesCaffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes SMOOTH MUSCLE, stimulates CARDIAC MUSCLE, stimulates DIURESIS, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide PHOSPHODIESTERASES, antagonism of ADENOSINE RECEPTORS, and modulation of intracellular calcium handling.Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Receptor Protein-Tyrosine Kinases: A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity.MAP Kinase Kinase 4: A mitogen-activated protein kinase kinase with specificity for JNK MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES and the RETINOID X RECEPTORS. It takes part in a SIGNAL TRANSDUCTION pathway that is activated in response to cellular stress.Radiation Tolerance: The ability of some cells or tissues to survive lethal doses of IONIZING RADIATION. Tolerance depends on the species, cell type, and physical and chemical variables, including RADIATION-PROTECTIVE AGENTS and RADIATION-SENSITIZING AGENTS.Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21.Phosphoprotein Phosphatases: A group of enzymes removing the SERINE- or THREONINE-bound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992)Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Mitogen-Activated Protein Kinases: A superfamily of PROTEIN-SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).Exodeoxyribonucleases: A family of enzymes that catalyze the exonucleolytic cleavage of DNA. It includes members of the class EC 3.1.11 that produce 5'-phosphomonoesters as cleavage products.Cyclin-Dependent Kinase 2: A key regulator of CELL CYCLE progression. It partners with CYCLIN E to regulate entry into S PHASE and also interacts with CYCLIN A to phosphorylate RETINOBLASTOMA PROTEIN. Its activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P27 and CYCLIN-DEPENDENT KINASE INHIBITOR P21.Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.Chromatin: The material of CHROMOSOMES. It is a complex of DNA; HISTONES; and nonhistone proteins (CHROMOSOMAL PROTEINS, NON-HISTONE) found within the nucleus of a cell.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Protein Transport: The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Xenopus Proteins: Proteins obtained from various species of Xenopus. Included here are proteins from the African clawed frog (XENOPUS LAEVIS). Many of these proteins have been the subject of scientific investigations in the area of MORPHOGENESIS and development.14-3-3 Proteins: A large family of signal-transducing adaptor proteins present in wide variety of eukaryotes. They are PHOSPHOSERINE and PHOSPHOTHREONINE binding proteins involved in important cellular processes including SIGNAL TRANSDUCTION; CELL CYCLE control; APOPTOSIS; and cellular stress responses. 14-3-3 proteins function by interacting with other signal-transducing proteins and effecting changes in their enzymatic activity and subcellular localization. The name 14-3-3 derives from numerical designations used in the original fractionation patterns of the proteins.Precipitin Tests: Serologic tests in which a positive reaction manifested by visible CHEMICAL PRECIPITATION occurs when a soluble ANTIGEN reacts with its precipitins, i.e., ANTIBODIES that can form a precipitate.Allyl CompoundsSubstrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.1-Phosphatidylinositol 4-Kinase: An enzyme that catalyzes the conversion of phosphatidylinositol (PHOSPHATIDYLINOSITOLS) to phosphatidylinositol 4-phosphate, the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate.Aphidicolin: An antiviral antibiotic produced by Cephalosporium aphidicola and other fungi. It inhibits the growth of eukaryotic cells and certain animal viruses by selectively inhibiting the cellular replication of DNA polymerase II or the viral-induced DNA polymerases. The drug may be useful for controlling excessive cell proliferation in patients with cancer, psoriasis or other dermatitis with little or no adverse effect upon non-multiplying cells.Endodeoxyribonucleases: A group of enzymes catalyzing the endonucleolytic cleavage of DNA. They include members of EC 3.1.21.-, EC 3.1.22.-, EC 3.1.23.- (DNA RESTRICTION ENZYMES), EC 3.1.24.- (DNA RESTRICTION ENZYMES), and EC 3.1.25.-.Phosphotransferases (Alcohol Group Acceptor): A group of enzymes that transfers a phosphate group onto an alcohol group acceptor. EC 2.7.1.Metaphase: The phase of cell nucleus division following PROMETAPHASE, in which the CHROMOSOMES line up across the equatorial plane of the SPINDLE APPARATUS prior to separation.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Glycogen Synthase Kinase 3: A glycogen synthase kinase that was originally described as a key enzyme involved in glycogen metabolism. It regulates a diverse array of functions such as CELL DIVISION, microtubule function and APOPTOSIS.I-kappa B Kinase: A protein serine-threonine kinase that catalyzes the PHOSPHORYLATION of I KAPPA B PROTEINS. This enzyme also activates the transcription factor NF-KAPPA B and is composed of alpha and beta catalytic subunits, which are protein kinases and gamma, a regulatory subunit.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Phosphothreonine: The phosphoric acid ester of threonine. Used as an identifier in the analysis of peptides, proteins, and enzymes.Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake.Isoenzymes: Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.Protein Kinase C-delta: A ubiquitously expressed protein kinase that is involved in a variety of cellular SIGNAL PATHWAYS. Its activity is regulated by a variety of signaling protein tyrosine kinase.Down-Regulation: A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.rho-Associated Kinases: A group of intracellular-signaling serine threonine kinases that bind to RHO GTP-BINDING PROTEINS. They were originally found to mediate the effects of rhoA GTP-BINDING PROTEIN on the formation of STRESS FIBERS and FOCAL ADHESIONS. Rho-associated kinases have specificity for a variety of substrates including MYOSIN-LIGHT-CHAIN PHOSPHATASE and LIM KINASES.Kinetics: The rate dynamics in chemical or physical systems.Ubiquitin-Protein Ligase Complexes: Complexes of enzymes that catalyze the covalent attachment of UBIQUITIN to other proteins by forming a peptide bond between the C-terminal GLYCINE of UBIQUITIN and the alpha-amino groups of LYSINE residues in the protein. The complexes play an important role in mediating the selective-degradation of short-lived and abnormal proteins. The complex of enzymes can be broken down into three components that involve activation of ubiquitin (UBIQUITIN-ACTIVATING ENZYMES), conjugation of ubiquitin to the ligase complex (UBIQUITIN-CONJUGATING ENZYMES), and ligation of ubiquitin to the substrate protein (UBIQUITIN-PROTEIN LIGASES).Anaphase-Promoting Complex-Cyclosome: An E3 ubiquitin ligase primarily involved in regulation of the metaphase-to-anaphase transition during MITOSIS through ubiquitination of specific CELL CYCLE PROTEINS. Enzyme activity is tightly regulated through subunits and cofactors, which modulate activation, inhibition, and substrate specificity. The anaphase-promoting complex, or APC-C, is also involved in tissue differentiation in the PLACENTA, CRYSTALLINE LENS, and SKELETAL MUSCLE, and in regulation of postmitotic NEURONAL PLASTICITY and excitability.Polyploidy: The chromosomal constitution of a cell containing multiples of the normal number of CHROMOSOMES; includes triploidy (symbol: 3N), tetraploidy (symbol: 4N), etc.Calcium-Binding Proteins: Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS.Protein Kinase C-alpha: A cytoplasmic serine threonine kinase involved in regulating CELL DIFFERENTIATION and CELLULAR PROLIFERATION. Overexpression of this enzyme has been shown to promote PHOSPHORYLATION of BCL-2 PROTO-ONCOGENE PROTEINS and chemoresistance in human acute leukemia cells.Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs.Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a CONSERVED SEQUENCE which can be represented by a CONSENSUS SEQUENCE.Gene Expression Regulation: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.Cyclin B1: A cyclin B subtype that colocalizes with MICROTUBULES during INTERPHASE and is transported into the CELL NUCLEUS at the end of the G2 PHASE.Chromosomal Instability: An increased tendency to acquire CHROMOSOME ABERRATIONS when various processes involved in chromosome replication, repair, or segregation are dysfunctional.Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.Recombination, Genetic: Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.Rad51 Recombinase: A Rec A recombinase found in eukaryotes. Rad51 is involved in DNA REPAIR of double-strand breaks.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Genes, Fungal: The functional hereditary units of FUNGI.Proto-Oncogene Proteins c-akt: A protein-serine-threonine kinase that is activated by PHOSPHORYLATION in response to GROWTH FACTORS or INSULIN. It plays a major role in cell metabolism, growth, and survival as a core component of SIGNAL TRANSDUCTION. Three isoforms have been described in mammalian cells.Diacylglycerol Kinase: An enzyme of the transferase class that uses ATP to catalyze the phosphorylation of diacylglycerol to a phosphatidate. EC 2.7.1.107.Gene Knockdown Techniques: The artificial induction of GENE SILENCING by the use of RNA INTERFERENCE to reduce the expression of a specific gene. It includes the use of DOUBLE-STRANDED RNA, such as SMALL INTERFERING RNA and RNA containing HAIRPIN LOOP SEQUENCE, and ANTI-SENSE OLIGONUCLEOTIDES.BRCA1 Protein: The phosphoprotein encoded by the BRCA1 gene (GENE, BRCA1). In normal cells the BRCA1 protein is localized in the nucleus, whereas in the majority of breast cancer cell lines and in malignant pleural effusions from breast cancer patients, it is localized mainly in the cytoplasm. (Science 1995;270(5237):713,789-91)Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.AMP-Activated Protein Kinases: Intracellular signaling protein kinases that play a signaling role in the regulation of cellular energy metabolism. Their activity largely depends upon the concentration of cellular AMP which is increased under conditions of low energy or metabolic stress. AMP-activated protein kinases modify enzymes involved in LIPID METABOLISM, which in turn provide substrates needed to convert AMP into ATP.Endonucleases: Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-.Protein Processing, Post-Translational: Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.Tyrosine: A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin.Radiation-Sensitizing Agents: Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Cyclins: A large family of regulatory proteins that function as accessory subunits to a variety of CYCLIN-DEPENDENT KINASES. They generally function as ENZYME ACTIVATORS that drive the CELL CYCLE through transitions between phases. A subset of cyclins may also function as transcriptional regulators.Topoisomerase I Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASE I.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Repressor Proteins: Proteins which maintain the transcriptional quiescence of specific GENES or OPERONS. Classical repressor proteins are DNA-binding proteins that are normally bound to the OPERATOR REGION of an operon, or the ENHANCER SEQUENCES of a gene until a signal occurs that causes their release.Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein TUBULIN and are influenced by TUBULIN MODULATORS.Focal Adhesion Kinase 1: A non-receptor protein tyrosine kinase that is localized to FOCAL ADHESIONS and is a central component of integrin-mediated SIGNAL TRANSDUCTION PATHWAYS. Focal adhesion kinase 1 interacts with PAXILLIN and undergoes PHOSPHORYLATION in response to adhesion of cell surface integrins to the EXTRACELLULAR MATRIX. Phosphorylated p125FAK protein binds to a variety of SH2 DOMAIN and SH3 DOMAIN containing proteins and helps regulate CELL ADHESION and CELL MIGRATION.Protein Phosphatase 2: A phosphoprotein phosphatase subtype that is comprised of a catalytic subunit and two different regulatory subunits. At least two genes encode isoforms of the protein phosphatase catalytic subunit, while several isoforms of regulatory subunits exist due to the presence of multiple genes and the alternative splicing of their mRNAs. Protein phosphatase 2 acts on a broad variety of cellular proteins and may play a role as a regulator of intracellular signaling processes.Myosin-Light-Chain Kinase: An enzyme that phosphorylates myosin light chains in the presence of ATP to yield myosin-light chain phosphate and ADP, and requires calcium and CALMODULIN. The 20-kDa light chain is phosphorylated more rapidly than any other acceptor, but light chains from other myosins and myosin itself can act as acceptors. The enzyme plays a central role in the regulation of smooth muscle contraction.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.CDC28 Protein Kinase, S cerevisiae: A protein kinase encoded by the Saccharomyces cerevisiae CDC28 gene and required for progression from the G1 PHASE to the S PHASE in the CELL CYCLE.Androstadienes: Derivatives of the steroid androstane having two double bonds at any site in any of the rings.Replication Origin: A unique DNA sequence of a replicon at which DNA REPLICATION is initiated and proceeds bidirectionally or unidirectionally. It contains the sites where the first separation of the complementary strands occurs, a primer RNA is synthesized, and the switch from primer RNA to DNA synthesis takes place. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)Janus Kinase 2: A Janus kinase subtype that is involved in signaling from GROWTH HORMONE RECEPTORS; PROLACTIN RECEPTORS; and a variety of CYTOKINE RECEPTORS such as ERYTHROPOIETIN RECEPTORS and INTERLEUKIN RECEPTORS. Dysregulation of Janus kinase 2 due to GENETIC TRANSLOCATIONS have been associated with a variety of MYELOPROLIFERATIVE DISORDERS.Aurora Kinase A: An aurora kinase that localizes to the CENTROSOME during MITOSIS and is involved in centrosome regulation and formation of the MITOTIC SPINDLE. Aurora A overexpression in many malignant tumor types suggests that it may be directly involved in NEOPLASTIC CELL TRANSFORMATION.Focal Adhesion Protein-Tyrosine Kinases: A family of non-receptor, PROLINE-rich protein-tyrosine kinases.Ribosomal Protein S6 Kinases, 90-kDa: A family of ribosomal protein S6 kinases that are structurally distinguished from RIBOSOMAL PROTEIN S6 KINASES, 70-KDA by their apparent molecular size and the fact they contain two functional kinase domains. Although considered RIBOSOMAL PROTEIN S6 KINASES, members of this family are activated via the MAP KINASE SIGNALING SYSTEM and have been shown to act on a diverse array of substrates that are involved in cellular regulation such as RIBOSOMAL PROTEIN S6 and CAMP RESPONSE ELEMENT-BINDING PROTEIN.MAP Kinase Kinase 2: A 44 kDa mitogen-activated protein kinase kinase with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.

A novel genetic screen for snRNP assembly factors in yeast identifies a conserved protein, Sad1p, also required for pre-mRNA splicing. (1/1039)

The assembly pathway of spliceosomal snRNPs in yeast is poorly understood. We devised a screen to identify mutations blocking the assembly of newly synthesized U4 snRNA into a functional snRNP. Fifteen mutant strains failing either to accumulate the newly synthesized U4 snRNA or to assemble a U4/U6 particle were identified and categorized into 13 complementation groups. Thirteen previously identified splicing-defective prp mutants were also assayed for U4 snRNP assembly defects. Mutations in the U4/U6 snRNP components Prp3p, Prp4p, and Prp24p led to disassembly of the U4/U6 snRNP particle and degradation of the U6 snRNA, while prp17-1 and prp19-1 strains accumulated free U4 and U6 snRNA. A detailed analysis of a newly identified mutant, the sad1-1 mutant, is presented. In addition to having the snRNP assembly defect, the sad1-1 mutant is severely impaired in splicing at the restrictive temperature: the RP29 pre-mRNA strongly accumulates and splicing-dependent production of beta-galactosidase from reporter constructs is abolished, while extracts prepared from sad1-1 strains fail to splice pre-mRNA substrates in vitro. The sad1-1 mutant is the only splicing-defective mutant analyzed whose mutation preferentially affects assembly of newly synthesized U4 snRNA into the U4/U6 particle. SAD1 encodes a novel protein of 52 kDa which is essential for cell viability. Sad1p localizes to the nucleus and is not stably associated with any of the U snRNAs. Sad1p contains a putative zinc finger and is phylogenetically highly conserved, with homologues identified in human, Caenorhabditis elegans, Arabidospis, and Drosophila.  (+info)

Caffeine can override the S-M checkpoint in fission yeast. (2/1039)

The replication checkpoint (or 'S-M checkpoint') control prevents progression into mitosis when DNA replication is incomplete. Caffeine has been known for some time to have the capacity to override the S-M checkpoint in animal cells. We show here that caffeine also disrupts the S-M checkpoint in the fission yeast Schizosaccharomyces pombe. By contrast, no comparable effects of caffeine on the S. pombe DNA damage checkpoint were seen. S. pombe cells arrested in early S phase and then exposed to caffeine lost viability rapidly as they attempted to enter mitosis, which was accompanied by tyrosine dephosphorylation of Cdc2. Despite this, the caffeine-induced loss of viability was not blocked in a temperature-sensitive cdc2 mutant incubated at the restrictive temperature, although catastrophic mitosis was prevented under these conditions. This suggests that, in addition to S-M checkpoint control, a caffeine-sensitive function may be important for maintenance of cell viability during S phase arrest. The lethality of a combination of caffeine with the DNA replication inhibitor hydroxyurea was suppressed by overexpression of Cds1 or Chk1, protein kinases previously implicated in S-M checkpoint control and recovery from S phase arrest. In addition, the same combination of drugs was specifically tolerated in cells overexpressing either of two novel S. pombe genes isolated in a cDNA library screen. These findings should allow further molecular investigation of the regulation of S phase arrest, and may provide a useful system with which to identify novel drugs that specifically abrogate the checkpoint control.  (+info)

RAD53 regulates DBF4 independently of checkpoint function in Saccharomyces cerevisiae. (3/1039)

The Cdc7p and Dbf4p proteins form an active kinase complex in Saccharomyces cerevisiae that is essential for the initiation of DNA replication. A genetic screen for mutations that are lethal in combination with cdc7-1 led to the isolation of seven lsd (lethal with seven defect) complementation groups. The lsd7 complementation group contained two temperature-sensitive dbf4 alleles. The lsd1 complementation group contained a new allele of RAD53, which was designated rad53-31. RAD53 encodes an essential protein kinase that is required for the activation of DNA damage and DNA replication checkpoint pathways, and that is implicated as a positive regulator of S phase. Unlike other RAD53 alleles, we demonstrate that the rad53-31 allele retains an intact checkpoint function. Thus, the checkpoint function and the DNA replication function of RAD53 can be functionally separated. The activation of DNA replication through RAD53 most likely occurs through DBF4. Two-hybrid analysis indicates that the Rad53p protein binds to Dbf4p. Furthermore, the steady-state level of DBF4 message and Dbf4p protein is reduced in several rad53 mutant strains, indicating that RAD53 positively regulates DBF4. These results suggest that two different functions of the cell cycle, initiation of DNA replication and the checkpoint function, can be coordinately regulated through the common intermediate RAD53.  (+info)

A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. (4/1039)

Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. Much of our current understanding of checkpoints comes from genetic studies conducted in yeast. In the fission yeast Schizosaccharomyces pombe (Sp), SpRad3 is an essential component of both the DNA damage and DNA replication checkpoints. The SpChk1 and SpCds1 protein kinases function downstream of SpRad3. SpChk1 is an effector of the DNA damage checkpoint and, in the absence of SpCds1, serves an essential function in the DNA replication checkpoint. SpCds1 functions in the DNA replication checkpoint and in the S phase DNA damage checkpoint. Human homologs of both SpRad3 and SpChk1 but not SpCds1 have been identified. Here we report the identification of a human cDNA encoding a protein (designated HuCds1) that shares sequence, structural, and functional similarity to SpCds1. HuCds1 was modified by phosphorylation and activated in response to ionizing radiation. It was also modified in response to hydroxyurea treatment. Functional ATM protein was required for HuCds1 modification after ionizing radiation but not after hydroxyurea treatment. Like its fission yeast counterpart, human Cds1 phosphorylated Cdc25C to promote the binding of 14-3-3 proteins. These findings suggest that the checkpoint function of HuCds1 is conserved in yeast and mammals.  (+info)

Cdc25 inhibited in vivo and in vitro by checkpoint kinases Cds1 and Chk1. (5/1039)

In the fission yeast Schizosaccharomyces pombe, the protein kinase Cds1 is activated by the S-M replication checkpoint that prevents mitosis when DNA is incompletely replicated. Cds1 is proposed to regulate Wee1 and Mik1, two tyrosine kinases that inhibit the mitotic kinase Cdc2. Here, we present evidence from in vivo and in vitro studies, which indicates that Cds1 also inhibits Cdc25, the phosphatase that activates Cdc2. In an in vivo assay that measures the rate at which Cdc25 catalyzes mitosis, Cds1 contributed to a mitotic delay imposed by the S-M replication checkpoint. Cds1 also inhibited Cdc25-dependent activation of Cdc2 in vitro. Chk1, a protein kinase that is required for the G2-M damage checkpoint that prevents mitosis while DNA is being repaired, also inhibited Cdc25 in the in vitro assay. In vitro, Cds1 and Chk1 phosphorylated Cdc25 predominantly on serine-99. The Cdc25 alanine-99 mutation partially impaired the S-M replication and G2-M damage checkpoints in vivo. Thus, Cds1 and Chk1 seem to act in different checkpoint responses to regulate Cdc25 by similar mechanisms.  (+info)

Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl. (6/1039)

Cells from individuals with the recessive cancer-prone disorder ataxia telangiectasia (A-T) are hypersensitive to ionizing radiation (I-R). ATM (mutated in A-T) is a protein kinase whose activity is stimulated by I-R. c-Abl, a nonreceptor tyrosine kinase, interacts with ATM and is activated by ATM following I-R. Rad51 is a homologue of bacterial RecA protein required for DNA recombination and repair. Here we demonstrate that there is an I-R-induced Rad51 tyrosine phosphorylation, and this induction is dependent on both ATM and c-Abl. ATM, c-Abl, and Rad51 can be co-immunoprecipitated from cell extracts. Consistent with the physical interaction, c-Abl phosphorylates Rad51 in vitro and in vivo. In assays using purified components, phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. After I-R, an increase in association between Rad51 and Rad52 occurs in wild-type cells but not in cells with mutations that compromise ATM or c-Abl. Our data suggest signaling mediated through ATM, and c-Abl is required for the correct post-translational modification of Rad51, which is critical for the assembly of Rad51 repair protein complex following I-R.  (+info)

Basis for the checkpoint signal specificity that regulates Chk1 and Cds1 protein kinases. (7/1039)

Six checkpoint Rad proteins (Rad1, Rad3, Rad9, Rad17, Rad26, and Hus1) are needed to regulate checkpoint protein kinases Chk1 and Cds1 in fission yeast. Chk1 is required to prevent mitosis when DNA is damaged by ionizing radiation (IR), whereas either kinase is sufficient to prevent mitosis when DNA replication is inhibited by hydroxyurea (HU). Checkpoint Rad proteins are required for IR-induced phosphorylation of Chk1 and HU-induced activation of Cds1. IR activates Cds1 only during the DNA synthesis (S) phase, whereas HU induces Chk1 phosphorylation only in cds1 mutants. Here, we investigate the basis of the checkpoint signal specificity of Chk1 phosphorylation and Cds1 activation. We show that IR fails to induce Chk1 phosphorylation in HU-arrested cells. Release from the HU arrest following IR causes substantial Chk1 phosphorylation. These and other data indicate that Cds1 prevents Chk1 phosphorylation in HU-arrested cells, which suggests that Cds1 actively suppresses a repair process that leads to Chk1 phosphorylation. Cds1 becomes more highly concentrated in the nucleus only during the S phase of the cell cycle. This finding correlates with S-phase specificity of IR-induced activation of Cds1. However, constitutive nuclear localization of Cds1 does not enhance IR-induced activation of Cds1. This result suggests that Cds1 activation requires DNA structures or protein activities that are present only during S phase. These findings help to explain how Chk1 and Cds1 respond to different checkpoint signals.  (+info)

RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast. (8/1039)

Eukaryotic checkpoint genes regulate multiple cellular responses to DNA damage. In this report, we examine the roles of budding yeast genes involved in G2/M arrest and tolerance to UV exposure. A current model posits three gene classes: those encoding proteins acting on damaged DNA (e.g. RAD9 and RAD24), those transducing a signal (MEC1, RAD53 and DUN1) or those participating more directly in arrest (PDS1). Here, we define important features of the pathways subserved by those genes. MEC1, which we find is required for both establishment and maintenance of G2/M arrest, mediates this arrest through two parallel pathways. One pathway requires RAD53 and DUN1 (the 'RAD53 pathway'); the other pathway requires PDS1. Each pathway independently contributes approximately 50% to G2/M arrest, effects demonstrable after cdc13-induced damage or a double-stranded break inflicted by the HO endonuclease. Similarly, both pathways contribute independently to tolerance of UV irradiation. How the parallel pathways might interact ultimately to achieve arrest is not yet understood, but we do provide evidence that neither the RAD53 nor the PDS1 pathway appears to maintain arrest by inhibiting adaptation. Instead, we think it likely that both pathways contribute to establishing and maintaining arrest.  (+info)

Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange The protein kinase Chk2 (checkpoint kinase 2) is a major effector of the replication checkpoint. Chk2 activation is initiated by phosphorylation of Thr68, in the serine glutamine/threonine-glutamine cluster domain (SCD), by ATM. The phosphorylated SCD-segment binds to the FHA domain of a second Chk2 molecule, promoting dimerisation of the protein and triggering phosphorylation of the activation segment/T-loop in the kinase domain. We have now determined the structure of the kinase domain of human Chk2 in complexes with ADP and a small-molecule inhibitor debromohymenialdisine. The structure reveals a remarkable dimeric arrangement in which T-loops are exchanged between protomers, to form an active kinase conformation in trans. Biochemical data suggest that this dimer is the biologically active state promoted by ATM-phosphorylation, and also suggests a mechanism for dimerisation-driven activation of Chk2 by ...
TY - JOUR. T1 - Differential roles for checkpoint kinases in DNA damage-dependent degradation of the Cdc25A protein phosphatase. AU - Jin, Jianping. AU - Cambronne, Xiaolu. AU - Ye, Xin. AU - Livingstone, Mark. AU - Harper, J. Wade. PY - 2008/7/11. Y1 - 2008/7/11. N2 - In response to DNA damage, cells activate a signaling pathway that promotes cell cycle arrest and degradation of the cell cycle regulator Cdc25A. Cdc25A degradation occurs via the SCFβ-TRCP pathway and phosphorylation of Ser-76. Previous work indicates that the checkpoint kinase Checkpoint kinase 1 (Chk1) is capable of phosphorylating Ser-76 in Cdc25A, thereby promoting its degradation. In contrast, other experiments involving overexpression of dominant Chk2 mutant proteins point to a role for Chk2 in Cdc25A degradation. However, loss-of-function studies that implicate Chk2 in Cdc25A turnover are lacking, and there is no evidence that Chk2 is capable of phosphorylating Ser-76 in Cdc25A despite the finding that Chk1 and Chk2 ...
Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010 ...
TY - JOUR. T1 - CHEK2 variant I157T may be associated with increased breast cancer risk. AU - Kilpivaara, Outi. AU - Vahteristo, Pia. AU - Falck, Jacob. AU - Syrjäkoski, Kirsi. AU - Eerola, Hannaleena. AU - Easton, Douglas. AU - Bartkova, Jirina. AU - Lukas, Jiri. AU - Heikkilä, Päivi. AU - Aittomäki, Kristiina. AU - Holli, Kaija. AU - Blomqvist, Carl. AU - Kallioniemi, Olli. AU - Bartek, Jiri. AU - Nevanlinna, Heli. PY - 2004. Y1 - 2004. N2 - Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low‐penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population‐based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06-1.95, p = 0.021) than among population ...
Although overexpression of multiple ATP-binding cassette transporters has been reported in clinical samples, few studies have examined how coexpression of multiple transporters affected resistance to chemotherapeutic drugs. We therefore examined how coexpression of ABCB1 (P-glycoprotein) and ABCG2 contributes to drug resistance in a cell line model. HEK293 cells were transfected with vector-encoding full-length ABCB1, ABCG2, or a bicistronic vector containing both genes, each under the control of a separate promoter. Cells transfected with both transporters (B1/G2 cells) demonstrated high levels of both transporters, and uptake of both the ABCB1-specific substrate rhodamine 123 and the ABCG2-specific substrate pheophorbide a was reduced when examined by flow cytometry. B1/G2 cells were also cross-resistant to the ABCB1 substrate doxorubicin, the ABCG2 substrate topotecan, as well as mitoxantrone and the cell cycle checkpoint kinase 1 inhibitor prexasertib, both of which were found to be ...
Recombinant Checkpoint Kinase 1 (CHEK1) Protéine. Origine: Humain. Source: Baculovirus infected Insect Cells. Commandez ABIN457519.
Inhibition of ATR (a DNA damage checkpoint kinase) is currently being evaluated with radiotherapy and chemoradiation in patients with oesophageal cancer in the Cancer Research UK/MRC funded CHARIOT clinical study, whilst dose escalation is being evaluated in the SCOPE 2 clinical study. We have done initial in silico planning to show that protons significantly reduce the dose received by heart and lung and dose modelling to predict toxicity of dose escalation. Furthermore we have shown that heart substructures have a critical role in non-cancer related mortality.
CHK2 is a checkpoint kinase involved in the ATM-mediated response to double-strand DNA breaks. Its potential as a drug target is still unclear, but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC50 of 3 nmol/L and shows minimal cross-reactivity against a panel of kinases at 1 mu mol/L. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as shown by inhibition of CHK2 autophosphorylation at S516, band shift mobility changes, and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the ...
BCR-ABL+ B-ALL is only transiently responsive to current therapies (29), with a 5-y survival of ∼35% (30, 31). Given this low survival rate, additional therapies are needed. One approach that has not been well explored in this disease is checkpoint blockade-based immunotherapy. Checkpoint blockade works well in malignancies with many nonsynonymous mutations and can lead to improved long-term survival in patients with such cancers (4, 32-36). Presumably, this is because the increased number of nonsynonymous mutations allows for a concurrent increase in the number of neoantigen-specific T cells. Comparatively, in cancers with low numbers of nonsynonymous mutations, such as B-ALL (36), checkpoint blockade-based immunotherapy targeting the endogenous immune response is relatively unstudied. In fact, current paradigms suggest that cancers with low numbers of nonsynonymous mutations may not be effectively treated using anti-CTLA4 and anti-PD1 checkpoint blockade (35). In the present study, we show ...
Mouse anti Human Chk2 antibody, clone 4B7 recognizes human Serine/threonine-protein kinase Chk2, also known as Chk2, CHK2 checkpoint homol
The checkpoint kinases Chk1/Chk2 and the CDK inhibitor p21 are known to have important complementary roles in this process, in G2 arrest and cell cycle exit, respectively ...
View Notes - Week 3 Checkpoint Fiber Research from SCI/241 AAGH0JAD35 at University of Phoenix. Week 3 Checkpoint: Fiber Research What is the function of fiber in the body? Fiber assists the body in
CHEK2 encodes for a G2 checkpoint kinase which plays a critical role in DNA repair. Its mutation confers an increased risk of breast cancer.
Only do checkpoint, when the PVMs and SVMs output net packets are inconsistent, We also limit the min time between two continuous checkpoint action, to give VM a change to run. Signed-off-by: zhanghailiang ,[email protected], Signed-off-by: Li Zhijian ,[email protected], --- include/net/colo-nic.h , 2 ++ migration/colo.c , 32 ++++++++++++++++++++++++++++++++ net/colo-nic.c , 5 +++++ 3 files changed, 39 insertions(+) diff --git a/include/net/colo-nic.h b/include/net/colo-nic.h index 809726c..57c6719 100644 --- a/include/net/colo-nic.h +++ b/include/net/colo-nic.h @@ -20,4 +20,6 @@ void colo_proxy_destroy(enum colo_mode mode); void colo_add_nic_devices(NetClientState *nc); void colo_remove_nic_devices(NetClientState *nc); +int colo_proxy_compare(void); + #endif diff --git a/migration/colo.c b/migration/colo.c index 22d7df1..a7cead9 100644 --- a/migration/colo.c +++ b/migration/colo.c @@ -17,6 +17,13 @@ #include migration/migration-failover.h #include net/colo-nic.h +/* +* We should not do ...
4A9S: Benzimidazole Inhibitors of the Protein Kinase Chk2: Clarification of the Binding Mode by Flexible Side Chain Docking and Protein-Ligand Crystallography.
Finden Sie alle Bücher von Herausgegeben von Schönthal, Axel H. - Checkpoint Controls and Cancer. Bei der Büchersuchmaschine eurobuch.com können Sie antiquarische und Neubücher VERGLEICHEN UND SOFORT zum Bestpreis bestellen. 1617374261
Genprex Reports New Pre-Clinical Data Showing Strong Anti-Tumor Effect Of TUSC2 In Combination With PD-1 Checkpoint Blockade In Lung Cancer
CCT244747 is a potent, orally bioavailable and highly selective CHK1 inhibitor, with an IC50 of 7.7 nM; CCT244747 also abrogates G2 checkpoint with an IC50 of 29 nM ...
Choose Frequencies from the Calculation drop down. Processors as 1. Theory as B3LYP. 6-31G(d) as Basis set. Charge zero. Multiplicity 1. Output as Standard. Format as cartesian Check the checkpoint check box. ...
The cellular response to DNA damage is critical for maintenance of genomic integrity and inhibition of tumorigenesis. Mutations or aberrant expression of the E3 ubiquitin ligase EDD have been observed in a number of carcinomas and we recently reported that EDD modulates activity of the DNA damage checkpoint kinase, CHK2. Here, we demonstrate that EDD is necessary for G(1)/S and intra S phase DNA damage checkpoint activation and for the maintenance of G(2)/M arrest after double strand DNA breaks. Defective checkpoint activation in EDD-depleted cells led to radio-resistant DNA synthesis, premature entry into mitosis, accumulation of polyploid cells, and cell death via mitotic catastrophe. In addition to decreased CHK2 activation in EDD-depleted cells, the expression of several key cell cycle mediators including Cdc25A/C and E2F1 was altered, suggesting that these checkpoint defects may be both CHK2-dependent and -independent. These data support a role for EDD in the maintenance of genomic stability,
The DNA replication checkpoint is a complex signal transduction pathway, present in all eukaryotic cells, that functions to maintain genomic integrity and cell viability when DNA replication is perturbed. In Schizosaccharomyces pombe the major effector of the replication checkpoint is the protein kinase Cds1. Activation of Cds1 is known to require the upstream kinase Rad3 and the mediator Mrc1, but the biochemical mechanism of activation is not well understood. We report that the replication checkpoint is activated in two stages. In the first stage, Mrc1 recruits Cds1 to stalled replication forks by interactions between the FHA domain of Cds1 and specific phosphorylated Rad3 consensus sites in Mrc1. Cds1 is then primed for activation by Rad3-dependent phosphorylation. In the second stage, primed Cds1 molecules dimerize via phospho-specific interactions mediated by the FHA domains and are activated by autophosphorylation. This two-stage activation mechanism for the replication checkpoint allows for rapid
TY - JOUR. T1 - Undamaged DNA transmits and enhances DNA damage checkpoint signals in early embryos. AU - Peng, Aimin. AU - Lewellyn, Andrea L.. AU - Maller, James L.. PY - 2007/10/1. Y1 - 2007/10/1. N2 - In Xenopus laevis embryos, the midblastula transition (MBT) at the 12th cell division marks initiation of critical developmental events, including zygotic transcription and the abrupt inclusion of gap phases into the cell cycle. Interestingly, although an ionizing radiation-induced checkpoint response is absent in pre-MBT embryos, introduction of a threshold amount of undamaged plasmid or sperm DNA allows a DNA damage checkpoint response to be activated. We show here that undamaged threshold DNA directly participates in checkpoint signaling, as judged by several dynamic changes, including H2AX phosphorylation, ATM phosphorylation and loading onto chromatin, and Chk1, Chk2 phosphorylation and release from nuclear DNA. These responses on physically separate threshold DNA require γ-H2AX and are ...
VANCOUVER, Sept. 27, 2016- ProNAi Licenses Oncology Drug Targeting DNA Damage Response Checkpoint Kinase 1 (Chk1) from CRT Pioneer Fund, UK.
PMID 17517688] Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case-control study. [PMID 17508290] Genetic susceptibility to breast cancer. [PMID 17458694] Detection of the CHEK2 1100delC mutation by MLPA BRCA1/2 analysis: a worthwhile strategy for its clinical applicability in 1100delC low-frequency populations? [PMID 17428325] Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk. [PMID 17428320] Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study. ...
Schuler, F., Afreen, S., Manzl, C., Häcker, G., Erlacher, M.,Villunger, A. Checkpoint kinase 1 is essential for fetal and adult hematopoiesis. EMBO Reports. 2019; e47026. doi:10.15252/embr.201847026. ...
Conducting regular sobriety checkpoints can significantly reduce crashes that involve drivers who have consumed alcohol. This is the major finding of an international review by the Centers for Disease Control of 23 studies of checkpoints. The researchers found that checkpoints reduce "alcohol-related crashes and associated fatal and nonfatal injuries ... . Despite differences across studies in design, periods of observation, and outcome measures evaluated, the results were generally consistent in direction and size.". Sobriety checkpoints reduced the crashes involving alcohol by about 20 percent, the researchers found. They pointed to the effectiveness of checkpoints that were conducted at the city, state, and national levels. Checkpoints conducted on both urban and rural roads were effective, the CDC reported.. The researchers reviewed studies of two types of checkpoints - those involving random breath tests at which every driver passing through is tested and those at which police must have a ...
Excess Hsl7 overrides the DNA replication checkpoint. (A) Xenopus Hsl7 or β-globin mRNA was incubated in cycling extracts in the presence of aphidicolin (200
Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells.
InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.
This mapping shows where the WCAG 1.0 checkpoints appear in the 16 June 2003 Working Draft. The WCAG 2.0 Working Draft is prepared by the Web Content Accessibility Guidelines Working Group (WCAG WG) to show how more generalized (less HTML-specific) WCAG checkpoints might read. The Working Draft is not based on consensus of the WCAG Working Group nor has it gone through W3C process. Checkpoints in the WCAG 2.0 Working Draft in no way supersede the checkpoints in WCAG 1.0.. The Web Content Accessibility Guidelines Working Group is working carefully to enable organizations and individuals that are currently using WCAG 1.0 (which remains stable and referenceable at this time) to ensure that they will eventually be able to make a smooth transition to WCAG 2.0.. ...
Now, what factors affect checkpoint_age? When we execute queries that change pages (i.e., INSERT/UPDATE/DELETE), we perform writes to the log, we change pages, and checkpoint_age is growing. When we perform flushing of changed pages, checkpoint_age is going down.. So that means the main way we have to keep checkpoint_age within point T is to change the number of pages being flushed per second. That way, we can keep checkpoint_age down.. If this doesnt help-and checkpoint_age keeps growing beyone T toward "async"-we have a second control mechanism: We can add a delay into INSERT/UPDATE/DELETE operations. This way we prevent checkpoint_age from growing and reaching "async".. To summarize, the idea of our algorithm is : We keep checkpoint_age within point T by increasing or decreasing the number of pages flushed per second. If checkpoint_age continues to grow, we add "throttling" to prevent it. The throttling depends on the position of checkpoint_age - the closer to "async", the bigger the ...
Contact Us. Tel:732-484-9848. Fax:888-484-5008. Email:[email protected]. Add:1 Deer Park Dr, Suite Q,. Monmouth Junction, NJ 08852, USA. ...
... is a Statutory board located in Changi. A number of Government Agency and others business can be found in ALPS Checkpoint.
The entire event will be in the dark with a mixture of street and off road route options. It is perfect for those wanting to get prepared for the Spring Challenge at the end of September. Come along and bring your friends! These fun 2hour rogaine is suitable for gurus to newbies. Anybody that has a moderate level of fitness can participate. A high level of navigation ability is not required.. Rogaining involves teams of two to five members visit as many checkpoints as possible in the time allowed. Shorter duration rogaines often allow solo competitors. Checkpoints are scored differently depending on level of difficulty in reaching them; therefore teams choose a strategy (for example, to visit many low score checkpoints)and route selection becomes a vital component.. Teams travel entirely on foot, navigating by map and compass between checkpoints in terrain that varies from open farmland to hilly forest. Teams travel at their own pace and anyone from children to grandparents can experience the ...
Chk1 (phospho Ser317) antibody (checkpoint kinase 1) for ICC/IF, WB. Anti-Chk1 (phospho Ser317) pAb (GTX132170) is tested in Human samples. 100% Ab-Assurance.
In this new paper by Nir Hacohen et al., researchers found that by analyzing the DNA of tumors from patients who developed resistance to checkpoint therapy, they found changes in the DNA of a key gene that is critical for tumors to be detected by the immune system.
Edison, NJ (PRWEB) May 14, 2008 -- CheckPoint HR, LLC, an innovator and leading Administrative Service Organization (ASO) (http://www.checkpointhr.com/hrms/)
Plasmid pDONR223-CHEK2 from Dr. William Hahns lab contains the insert CHEK2 and is published in Nature. 2010 Nov 24. ():. This plasmid is available through Addgene.
Providing surgeons with state-of-the-art neurodevices to locate and identify nerves and evaluate nerve and muscle excitability in surgical procedures. ...
Circulation 2000; 1021027-32. 12 Checkpoints Regulate Transition Events in a Network The cycle of cell growth and division passes through four stages (Figure 14.
Any one cd $10 USA and $14 World Any two Cds $18 USA and $25 World Any 3 Cds $24 USA and $36 World Any 4 CDs $30 USA and $46 World More Than 4 cds 7.00 Each or
Heavy consumption of the essential amino acid lysine (as indicated in the treatment of cold sores) has allegedly shown false positives in some and was cited by American shotputter C. J. Hunter as the reason for his positive test, though in 2004 he
Nov 02, 2019 (Eon Market Research via COMTEX) -- The market report, titled Global Serine/Threonine Protein Kinase Chk1 Market Research Report 2019 - By Manufacturers, Product Type, Applications, Region and Forecast to 2026′, recently added to the market research repository of Eonmarketresearch.com, details in-depth past and present analytical and statistical data about the global Serine/Threonine Protein Kinase Chk1 market. The report describes the Serine/Threonine Protein Kinase Chk1 market in detail in terms of the economic and regulatory factors that are currently shaping the markets growth trajectory, the regional segmentation of the global Serine/Threonine Protein Kinase Chk1 market , and an analysis of the markets downstream and upstream value and supply chains. Competitive Research of Global Serine/Threonine Protein Kinase Chk1 Market 2019 Based on Key Players: " CanBas Co Ltd Cascadian Therapeutics Inc Eli Lilly and Company Genentech Inc ProNAi Therapeutics Inc Sareum Holdings Plc ...
A subtype of familial breast cancer that includes colorectal cancer was recognized by Lynch et al. already in 1972 [19] and recently the CHEK2 1100delC mutation was proposed to represent a low-penetrant breast cancer susceptibility allele [10, 11]. This variant has been identified at a particularly high frequency (18%) in families with a hereditary breast- and colorectal cancer phenotype [16]. Since development of multiple primary tumors is a hallmark of hereditary cancer and a high frequency of the CHEK2 1100delC had been described in hereditary breast and colorectal families, we assessed the contribution of this variant to the development of double primary breast and colorectal cancer in a population-based patient material. Among the 75 patients with metachronous tumors of the breast and the colorectum successfully studied, 2 (2.5%) carried the CHEK2 1100delC mutation compared to 1% in the control group [18]. These frequencies were not significantly different (p = 0.26), but the small size of ...
Faithful duplication and segregation of undamaged DNA is critical to the survival of all organisms and prevention of oncogenesis in multicellular organisms. To ensure inheritance of intact DNA, cells rely on checkpoints. Checkpoints alter cellular processes in the presence of DNA damage preventing cell cycle transitions until replication is completed or DNA damage is repaired. Several checkpoints are specific to S-phase. The S-M replication checkpoint prevents mitosis in the presence of unreplicated DNA. Rather than outright halting replication, the S-phase DNA damage checkpoint slows replication in response to DNA damage. This checkpoint utilizes two general mechanisms to slow replication. First, this checkpoint prevents origin firing thus limiting the number of replication forks traversing the genome in the presence of damaged DNA. Second, this checkpoint slows the progression of the replication forks. Inhibition of origin firing in response to DNA damage is well established, however when this thesis
In fiscal year 2008 thirty-nine tactical checkpoints were in operation. Tactical checkpoints lack permanent buildings, and "support permanent checkpoints by monitoring and inspecting traffic on secondary roads that the Border Patrol determined are likely to be used by individuals in the country illegally or smugglers to evade apprehension at permanent checkpoints". A tactical checkpoint might consist of vehicles, traffic cones, signs, a portable water supply, a cage for canines (if deployed), and portable rest facilities.[2]. Due to Congressional restrictions against the funding of permanent checkpoints in the Tucson sector, all of its checkpoints are tactical checkpoints. These were required to relocate every seven days, amended to every 14 days in 2005. Due to the need for road shoulder space and restrictions on placing checkpoints near curves, the number of sites is limited, and the relocation in practice means that checkpoints are periodically shut down. In 2005, the median tactical ...
Marian Blanca Ramírez from the CSIC in Spain has been studying the effects of LRRK2, a protein associated with Parkinsons disease, on cell motility. A Travelling Fellowship from Journal of Cell Science allowed her to spend time in Prof Maddy Parsons lab at Kings College London, learning new cell migration assays and analysing fibroblasts cultured from individuals with Parkinsons. Read more on her story here. Where could your research take you? The deadline to apply for the current round of Travelling Fellowships is 23rd Feburary 2018. Apply now!. ...
The reports includes global Checkpoint Inhibitors for Treating Cancer market drivers, challanges, constraints, opportunities, investment potential, leading technologies, future guidelines, Checkpoint Inhibitors for Treating Cancer industry player profile, regulatory ecosystem and plans. The report also delivers market size forecasts for Checkpoint Inhibitors for Treating Cancer market. The forecasts are further mentioned in the top segment of Checkpoint Inhibitors for Treating Cancer market. This report lists out some of the major key trends that are expected to influence the overall Checkpoint Inhibitors for Treating Cancer market development and also presents market statistics to study predominant market trends. In this report, Checkpoint Inhibitors for Treating Cancer market is segmented on the basis of application, type, end use and regions. In addition, the report presents detailed information regarding major revenue generating regions of Checkpoint Inhibitors for Treating Cancer ...
The frequency of the CHEK2 1100delC among colorectal cancer patients was 2.6% (17/662). The proportions were 1.3% (2/149) and 2.9% (15/513) in familial and non-familial cases, respectively. These frequencies are not significantly higher (odds ratio (OR) 1.393, 95% confidence interval (CI) 0.775 to 2.504, p=0.266, for all cases; OR 0.720, 95% CI 0.172 to3.020, p=1.000 for familial cases and OR 1.592, 95% CI 0.863 to 2.939, p=0.134 for non-familial cases) than in the normal population, compared with the geographically adjusted population frequency of 1.9%. These results suggest that the 1100delC variant is not significantly associated with familial colorectal cancer or with colorectal cancer risk in the population; however, larger studies would be needed to detect or exclude any slight increase with a high confidence. In the group of non-familial colorectal cancer cases, there was no difference in allele frequency among those patients with a personal or family history of breast cancer (3/104, ...
In this report, we have compared cell cycle responses of the human breast carcinoma MA-11 cell line to ionizing radiation and HDAC inhibition. Whereas accumulation of G2-M phase cells, as well as the preceding repression of the genes encoding the G2 phase regulators Plk1 and cyclin B1, after irradiation required intact G2 checkpoint signaling through the checkpoint kinase CHK1, the similar phenotypic changes observed with HDAC inhibition did not. MA-11 cells did not show radiation-dependent induction of the G1 phase inhibitor p21, indicative of a defective G1 checkpoint and possibly consistent with the base substitution detected in the tumor suppressor TP53 gene. Induction of p21, however, was observed with HDAC inhibition. Following pretreatment with the HDAC inhibitor, the efficiency of clonogenic regrowth after irradiation was reduced, which is in accordance with the concept of increased probability of mitotic cell death when the chromatin structure is disrupted.. Recent reports have shown ...
SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of important cell cycle checkpoints and central mediator of the DNA Damage Response network. In cancer cells, replication stress induced by oncogenes (e.g., MYC and RAS) or genetic mutations in DNA repair machinery (e.g. BRCA1 and FA) combined with loss of function in tumor suppressors (e.g., TP53 and ATM) results in persistent DNA damage and genomic instability leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to these cancer cells.. The study has been designed to investigate the safety and tolerability of SRA737; to determine the pharmacokinetics of SRA737; to identify the optimal dose, schedule, and maximum tolerated dose (MTD); to obtain preliminary evidence of activity; and to evaluate preliminary efficacy in prospectively-screened, genetically-selected subjects.. This clinical study ...
Che-1 is a RNA polymerase II binding protein involved in the regulation of gene transcription, and in response to DNA damage promotes p53 transcription. In this study, we investigated whether Che-1 regulates mutant p53 expression. We found that Che-1 is required for sustaining mutant p53 expression in several cancer cell lines, and Che-1 depletion by siRNA induces apoptosis both in vitro and in vivo. Notably, loss of Che-1 activates DNA damage checkpoint response and induces transactivation of p73. Therefore, these findings suggest a new therapeutic approach that allowing simultaneous modulation of p73 and mutant p53 levels might be used to target the large fraction of human tumors harboring p53 mutations.. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2983. ...
PMID: 25593928, PMCID: PMC4292055. "Preserved DNA damage checkpoint pathway protects against complications in long-standing type 1 diabetes," S. Bhatt, M. K. Gupta, M. Khamaisi, R. Martinez, M. A. Gritsenko, B. K. Wagner, P. Guye, V. Busskamp, J. Shirakawa, G. Wu, C. W. Liew, T. R. Clauss, I. Valdez, A. El Ouaamari, E. Dirice, T. Takatani, H. A. Keenan, R. D. Smith, G. Church, R. Weiss, A. J. Wagers, W. -J. Qian, G. L. King, and R. N. Kulkarni, Cell Metab. 22 (2): 239-252 (2015 ...
In response to genotoxic stress, the DNA damage response, which is governed primarily by the ATM-CHK2, ATR-CHK1, and p38-MK2 (also known as MAPKAPK2) checkpoint effector pathways, becomes activated in order to slow cell-cycle progression and allow time for DNA repair. The CHK1 and MK2 pathways converge on inhibition of cell division cycle 25 (CDC25)-mediated activation of cyclin-dependent kinases, prompting Dietlein and colleagues to hypothesize that simultaneous small-molecule inhibition of CHK1 and MK2 may synergistically silence the DNA damage checkpoint. To systematically characterize combinatorial drug-inhibitor relationships, 96 cancer cell lines were screened with various concentrations of the CHK1 inhibitor PF477736 and the MK2 inhibitor PF3644022, and PreCISE (predictor of chemical inhibitor synergistic effects) software was used to calculate synergism scores based on GI50 drug curves. Synergistic effects between PF477736 and PF3644022 were observed in 33 of 96 cell lines and were ...
Figure 1. High‐throughput siRNA screen identifies kinases that regulate the ionizing‐radiation‐induced G2 checkpoint. (A) Schematic overview of the robot‐automated high‐throughput siRNA screen. p53 dominant‐negative U2OS (U2OS p53dneg) cells were reverse transfected and, after incubation for 2 days, treated with 6 Gy of IR and, 2 h later, with nocodazole for 8 h and subsequently stained with H3Ser10p antibody to stain mitotic cells, and Hoechst to stain the nuclei. (B) Flow cytometric analysis of U2OS p53dneg cells. Where indicated, cells were treated with IR (6 Gy) and 2 h later with nocodazole for 8 h. Cells were collected and stained with phospho H3ser10 (H3Ser10p) antibody and propidium iodide (PI). (C) CHK1 depletion abrogates the G2 checkpoint. U2OS p53dneg cells were transfected with CHK1 siRNA and treated with IR (6 Gy) and 2 h later with nocodazole for 8 h. Top panel: immunofluorescence microscopy images obtained from the robot‐automated screen. Bottom panel: cells were ...
AZD7762 is a potent ATP-competitive checkpoint kinase inhibitor with an IC50 of 5 and <10 nM for CHK1 and CHK2 respectively. Buy Checkpoint inhibitor AZD7762 from AbMole BioScience.
p53 is a critical regulator of both the G1 and G2 cellular checkpoints (Bunz et al., 1998). Given that mutations of p53 are observed in approximately 50% of tumors (Hollstein et al., 1999), which are therefore defective in the G1 checkpoint, selective inhibition of the G2 checkpoint may be useful in cancer therapy by enhancing the effects of DNA-damaging agents (Nurse, 1997; Roberge et al., 1998). G2 inhibitors, including caffeine, staurosporine, and UCN-01, and selective Chk1 inhibitors have been shown to enhance the cytotoxicity of DNA-damaging agents (Bunch and Eastman, 1996; Bunz et al., 1998; Roberge et al., 1998; Hollstein et al., 1999; Tse et al., 2007). The observation that G2 inhibitors enhance the effects of DNA-damaging agents supports the rationale for using a specific inhibitor of Chk2 in cells defective in the G1 checkpoint. Moreover, specific Chk2 inhibitors may reduce the side effects commonly associated with chemo/radiotherapy as they may inhibit the p53-induced apoptotic ...
The human Rad9A checkpoint protein is required for genomic stability and proper execution of the DNA damage checkpoint. Previous work has shown Rad9A to be the key member of a heterotrimeric toroidal structure known as ...
Use of antibiotics up to a month before treatment with a checkpoint inhibitor may decrease the efficacy of the immunotherapy agent, results of a retrospective analysis show.
CELL CYCLE CHECKPOINTS The cell cycle has regulatory points called checkpoint. A check point is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cell cycle can be halted until conditions are favourable (e.g. the DNA is repaired). These checkpoints occur near […]. ...
Mouse polyclonal antibody raised against a full-length human CHEK1 protein. CHEK1 (ABM87141.1, 1 a.a. ~ 476 a.a) full-length human protein. (H00001111-B02P) - Products - Abnova
Apoptosis induction by Chk1 or SAC inhibition.A. Chk1 inhibition by a dominant-negative (DN) Chk1 mutant. Diploid or tetraploid HCT116 cells were transfected wi
DI-fusion, le Dépôt institutionnel numérique de lULB, est loutil de référencementde la production scientifique de lULB.Linterface de recherche DI-fusion permet de consulter les publications des chercheurs de lULB et les thèses qui y ont été défendues.
Gov will do what we allow. The general acceptance of searches without probable cause has led to the expansion of these searches. Gov will not limit itself. In fact, the past has shown the opposite to be true. Only we can limit power. One by one, we must resist by demanding our rights be recognized. If we hold up the line by asking: Am I under arrest? No? Am I free to go? and I do not consent to be searched., then we are doing our part to stop tyranny. Anything less is silent approval ...
Dun Chonallaich (Hillfort) on The Modern Antiquarian, the UK & Irelands most popular megalithic community website. 14 images, 1 fieldnote, plus information on many more ancient sites nearby and across the UK & Ireland.
Genome integrity is vulnerable during DNA replication. The act of replication can convert a relatively benign single-strand DNA break to a cytotoxic double-strand break. A cyclobutane dimer, formed by UV irradiation, is sufficient to block the progression of DNA polymerases and to cause replication fork collapse (17). To cope with these problems, eukaryotic organisms have developed mechanisms for replicating DNA through and around damage in ways that cause minimal genome instability. Notable among the proteins involved in these processes are lesion bypass polymerases that can replicate through cyclobutane dimers (45). Recombination and double-strand break repair enzymes are also important, participating in the direct repair of DNA structure abnormalities that arise during DNA replication or permitting continued replication around sites of damage (17). These systems, and perhaps others that remain undiscovered, collectively form a genome defense system that allows tolerance of damage during DNA ...
As described above, checkpoint proteins play critical roles in responding to uncapped telomeres. Blackburn and others have proposed that capped telomeres prevent telomerase, DNA repair and checkpoint pathways from being activated, whereas uncapped telomeres activate telomerase, repair and checkpoint pathways (Blackburn, 2000; Blackburn, 2001; Chan and Blackburn, 2002). According to these models uncapped telomeres are short lived because telomerase rapidly restores the telomere length required for capping. However, the question remains as to how a cell distinguishes between telomeric and DSB ends such that telomeres induce telomerase-dependent rather than repair-dependent pathways to heal the end.. Building on the concept of capped and uncapped telomeres, I suggest that telomeres may vary between the extremes of capped, telomere-like states, and uncapped, DSB-like states. Fig. 3 illustrates this model and is based on the finding that at least four seemingly different DNA damage checkpoint ...
The protein encoded by this gene belongs the PI3/PI4-kinase family, and is most closely related to ATM, a protein kinase encoded by the gene mutated in ataxia telangiectasia. This protein and ATM share similarity with Schizosaccharomyces pombe rad3, a cell cycle checkpoint gene required for cell cycle arrest and DNA damage repair in response to DNA damage. This kinase has been shown to phosphorylate checkpoint kinase CHK1, checkpoint proteins RAD17, and RAD9, as well as tumor suppressor protein BRCA1. Mutations of this gene are associated with Seckel syndrome. An alternatively spliced transcript variant of this gene has been reported, however, its full length nature is not known. Transcript variants utilizing alternative polyA sites exist. [provided by RefSeq, Jul 2008 ...
MCC is a potential tumor suppressor gene, which is silenced by promoter hypermethylation in a subset of colorectal cancers. However, its functions have remained poorly understood. In the present study, we describe a novel function of MCC in the DNA damage response. Several novel phosphorylation sites were identified by mass spectrometry, including 2 highly conserved ATM/ATR consensus sites at serine 118 and serine 120. In addition, exposure to ultraviolet radiation (UV), but not phleomycin, caused PI3K-dependent phosphorylation of MCC and its nuclear localization. Re-expression of MCC in HCT15 colorectal cancer cells led to a G2/M arrest, and MCC knockdown impaired the induction of a G2/M arrest following UV radiation. Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. Thus, these results suggest that MCC is a novel target of the DNA damage checkpoint and that MCC is required for the complete cell cycle arrest in the G2
After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins. p53 is an important downstream target of ATM and ATR, as it is required for inducing apoptosis following DNA damage.[33] At the G1/S checkpoint, p53 functions by deactivating the CDK2/cyclin E ...
One function of cell cycle checkpoints is to integrate cell cycle progression with DNA replication and repair. Therefore, the integrity of these checkpoints is considered essential in maintaining genetic stability. Mutations in checkpoint components may lead to aberrant cell cycle progression and, in the presence of DNA damage, may lead to subsequent genetic instability. DNA damage triggers a variety of cellular responses, including activation of DNA damage response pathways. In fission yeast, genetic evidence pointed to a model in which five checkpoint Rad proteins, Rad1, Rad9, Rad17, Rad26, and Hus1, sense DNA alterations and then cooperate to send a signal through Rad3 (1) . Rad3 can also function in the absence of several of these Rad genes, suggesting that Rad3 may interact with other proteins involved in the DNA damage response (4) .. In S. pombe the cell cycle checkpoint gene Rad1 is required to ensure that mitosis does not occur in the presence of DNA damage (8 , 9) . X-Spy1 was ...
In this study, we addressed two aspects of the role of MEI-41 in DSB repair: (1) which specific DSB repair processes are influenced by loss of MEI-41 and (2) whether the checkpoint function of MEI-41 accounts for defects in repair observed in mei-41 mutants. Our results indicate that loss of MEI-41 affects repair by HR, but not by NHEJ, and that the disruption of HR cannot be explained entirely by loss of the GRP/LOK-mediated G2-M DNA damage checkpoint. This suggests that MEI-41 regulates repair through a mechanism independent of the GRP/LOK-mediated checkpoint response.. Evidence that the effect of loss of MEI-41 is specific to HR comes from our finding that lethality of mei-41 mutants undergoing P-element excision is eliminated through use of spn-A mutations. A previous study suggested that repair of DSBs generated by P-element excision in somatic tissues occurs primarily through NHEJ (Gloor et al. 2000), but our results indicate that repair by HR is also important, at least in some essential ...
NEW YORK, Oct. 03, 2016 (GLOBE NEWSWIRE) - Checkpoint Therapeutics, Inc. ("Checkpoint"), a Fortress Biotech (NASDAQ:FBIO) company, today announced that the first patient has been dosed in a Phase 1/2 clinical study of CK-101, its novel, oral, third-generation epidermal growth factor receptor ("EGFR") inhibitor product candidate. The Phase 1 dose escalation portion of the study will evaluate the safety and tolerability of ascending doses of CK-101 in patients with advanced solid tumors to determine the maximum tolerated dose and/or recommended Phase 2 dose of CK-101. The Phase 2 portion of the study is planned to evaluate the safety and efficacy of the recommended Phase 2 dose of CK-101 in patients with EGFR T790M mutation-positive non-small cell lung cancer. "This is a very exciting time for Checkpoint, with the initiation of our first clinical program for a product candidate in our portfolio," said James F. Oliviero, III, President and CEO of Checkpoint Therapeutics. "We believe there is a need ...
For speedy, intra-operative pathological margin assessment to steer staged cancers excisions, multimodal confocal mosaic check picture wide surgical margins (approximately 1?cm) with sub-cellular resolution and mimic the appearance of conventional hematoxylin and eosin histopathology (H&E). The goal of this work is definitely to combine three confocal imaging modes: acridine orange fluorescence (AO) for labeling nuclei, […]. ...
Cancer and tumor cells are difficult to fight and require your body to generate a proper inflammatory response in order to clear them. However, the situation is made all the more difficult by cell markers that can induce tolerance in your T cells. These immune checkpoints are becoming hot topics for potential antibody therapies. Learn more these emerging factors with our Immune Checkpoints webpage. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.
For many lung cancer patients, the best treatment options involve checkpoint inhibitors. These drugs unleash a patients immune system against their disease and can yield dramatic results, even in advanced cancers.. But checkpoint inhibitors come with a huge caveat: They only help a small subset of patients. Doctors struggle to predict who these patients are and-just as important-who they arent.. Results from a new study published in the journal JCI Insight could help improve those forecasts (2019; doi: 10.1172/jci.insight.130850).. After analyzing tumor samples from 28 patients with non-small cell lung cancer, researchers linked a common immune cell with treatment failure. The culprit: neutrophils, the most abundant type of white blood cell.. The paper shows that the balance between neutrophils and another type of immune cell-disease-fighting T cells-could accurately predict which patients would respond or not. If more neutrophils than T cells were crowded into a tumor, the drugs did not curb ...
Nollette said police had received reports that protesters allegedly set up barricades, " with some armed individuals running them as checkpoints into the neighborhood." "While they have a constitutionally-protected right to bear arms, and while Washington is an open carry state, there is no legal right for those arms to be used to intimidate community members," Nollette said, adding that anyone subjected to these demands should call 911. "No one at these checkpoints has the legal authority to demand identification from anyone." Nollette also said police have "heard anecdotally" of residents and businesses being asked to pay a fee if they want to operate in the area. "This is the crime of extortion," Nollette said ...
epigenetic regulation of apoptosis and cell cycle in, frontiers the dna damage response in mammalian oocytes, cell cycle checkpoint, biobook leaf what happens at each of the cell cycle, 301 moved permanently
numerous post-translational modifications lead to stabil- In contrast to the key role of p53 in maintenance of the isation of the p53 protein and activation of its DNA-induced G1 arrest, no specific roles for p53 or p21 sequence-specific DNA binding [9,30]. Only then can p53 have been implicated in the control of the intra-S-phase efficiently stimulate transcription of cell-cycle inhibitors checkpoint. This is perhaps not so surprising as the such as p21 (Figure 2). Furthermore, the p21 protein has to S-phase checkpoint, manifested by a decreased rate of accumulate to levels sufficiently high to inhibit the CDK- DNA synthesis after generation of DSBs, is by definition a containing complexes, before cell-cycle progression transient phenomenon [5]. The absence of the mainte- becomes efficiently blocked. Although p53 has recently nance component during S phase, contrary to the G1 and been described binding to 5′ untranslated region of CDK4 G2 checkpoints, might be beneficial for the cells by ...
HEIDELBERG, Germany, Dec. 6, 2015-- Affimed N.V., a clinical-stage biopharmaceutical company developing highly targeted cancer immunotherapies, today presented preclinical data on the potency and efficacy of the combination of the Companys NK-cell-engaging TandAb, AFM13, with various checkpoint inhibitors, including further data with a marketed...
An anonymous reader writes New security check points in 2020 will look just like something out of the futuristic movie, The Minority Report. The idea of the new checkpoints will allow high traffic to pass through just as you were walking at a normal pace. No more waving a wand to get through checkp...
Recombinant Human full length check point kinase 2 with N-terminal His-tag was expressed in a Baculovirus infectedSf9 cellexpression system. MW=91kDa.
Due to restrictions on geographic data in China, all Chinese map services provide distorted maps that are shifted from GeoHacks coordinates. You may obtain corrected coordinates for these maps from this link. (Use "WGS → BD" for Baidu and "WGS → GCJ" for all other services including Google ...
Limited Supply. 1991. E. Short. The author, a 20 year veteran of science fairs, endeavors to lead children, teachers, and parents on the road to a sucessful (and painless) …
There are about 30 TCGA workunits still around and for sure those are the very long ones. Theoretically those could run forever. The reason is that for a certain, very rare, type of input the algorithms completely is exponential. We usually manage to adjust the input dataset in order to avoid this but in the current case there were an issue that we were able to fix only after the workunits were distributed. The results are of scientific value, of course, but without a checkpoint inside the critical section of the algorithm this is not the kind of computation to do inside the BOINC framework ...
Coordination of the multiple processes underlying DNA replication is key for maintaining genome stability and preventing tumorigenesis. CLASPIN, a critical player in replication fork stabilization and checkpoint responses, must be tightly regulated during the cell cycle to prevent the accumulation of DNA damage. In this study, we used a quantitative proteomics approach and identified USP9X as a novel CLASPIN-interacting protein. USP9X is a deubiquitinase involved in multiple signaling and survival pathways whose tumor suppressor or oncogenic activity is highly context dependent. We found that USP9X regulated the expression and stability of CLASPIN in an S-phase-specific manner. USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive endogenous DNA damage. Importantly, restoration of CLASPIN expression in USP9X-depleted cells partially suppressed the accumulation of ...
The Mre11-Rad50-Nbs1 (MRN) complex has many biological functions: processing of double-strand breaks in meiosis, homologous recombination, telomere maintenance, S-phase checkpoint, and genome stability during replication. In the S-phase DNA damage checkpoint, MRN acts both in activation of checkpoint signaling and downstream of the checkpoint kinases to slow DNA replication. Mechanistically, MRN, along with its cofactor Ctp1, is involved in 5 resection to create single-stranded DNA that is required for both signaling and homologous recombination. However, it is unclear whether resection is essential for all of the cellular functions of MRN. To dissect the various roles of MRN, we performed a structure-function analysis of nuclease dead alleles and potential separation-of-function alleles analogous to those found in the human disease ataxia telangiectasia-like disorder, which is caused by mutations in Mre11. We find that several alleles of rad32 (the fission yeast homologue of mre11), along with
Pif1, an evolutionarily conserved helicase, negatively regulates telomere length by removing telomerase from chromosome ends. Pif1 has also been implicated in DNA replication processes Such as Okazaki fragment maturation and replication fork pausing. We find that overexpression of Saccharomyces cervisiae results in dose-dependent. growth inhibition. Strong overexpression causes relocalization of the DNA damage response factors Rfa1 and Mre11 into nuclear foci and activation of the Rad53 DNA damage checkpoint kinase, indicating that. the toxicity is caused by accumulation of DNA-damage. We screened the complete set of similar to 4800 haploid gene deletion mutants and found that moderate overexpression of PIF1, which is only mildly toxic oil its own, causes growth defects in strains with Mutations in genes involved in DNA replication and the DNA damage response. Interestingly, we find that telomerase-deficient strains are also sensitive to PIF1 overexpression. Cur data are consistent with a model ...
Proteins involved in the DNA damage response accumulate as microscopically-visible nuclear foci on the chromatin flanking DNA double-strand breaks (DSBs). As growth of ionizing radiation (IR)-induced foci amplifies the ATM-dependent DNA damage signal, the formation of discrete foci plays a crucial role in cell cycle checkpoint activation, especially in cells exposed to lower doses of IR. However, there is no quantitative parameter for the foci which considers both the number and their size. Therefore, we have developed a novel parameter for DNA damage signal based on the image analysis of the foci and quantified the amount of the signal sufficient for G2 arrest. The parameter that we have developed here was designated as SOID. SOID is an abbreviation of Sum Of Integrated Density, which represents the sum of fluorescence of each focus within one nucleus. The SOID was calculated for individual nucleus as the sum of (area (total pixel numbers) of each focus) x (mean fluorescence intensity per pixel of each
The ubiquitin family member Sumo has important functions in many cellular processes including DNA repair, transcription and cell division. Numerous studies have shown that Sumo is essential for maintaining cell homeostasis when the cell encounters endogenous or environmental stress, such as osmotic stress, hypoxia, heat shock, genotoxic stress, and nutrient stress. Regulation of transcription is a key component of the Sumo stress response, and multiple mechanisms have been described by which Sumo can regulate transcription. Although many individual substrates have been described that are sumoylated during the Sumo stress response, an emerging concept is modification of entire complexes or pathways by Sumo. This review focuses on the function and regulation of Sumo during the stress response.
Immune checkpoints are one of the protective mechanisms in normal organisms. Under the initiation of the usual immune system, T cells can perform antigen-specific cytotoxicity and guide other immune responses against foreign organisms with antigens different from the host itself; however, such functions need to have a set of regulatory functions to avoid causing autoimmune reactions or injuring their own cells or tissues when fighting foreign cells. This set of regulatory functions, which we call immune checkpoint mechanisms, simply means that different groups of ligand and receptor reactions increase or inhibit the immune effects of T cells.. With years experience, Creative BioMart provides a wide range of immune checkpoint proteins and the bio-activity of all those products has been assayed and confirmed, making them essential materials for mechanistic studies and development of new therapeutics.. Creative BioMart immune checkpoint proteins mainly include: 2B4, 4-1BB, 4-1 BB Ligand, B7-1, ...
Immune checkpoints are one of the protective mechanisms in normal organisms. Under the initiation of the usual immune system, T cells can perform antigen-specific cytotoxicity and guide other immune responses against foreign organisms with antigens different from the host itself; however, such functions need to have a set of regulatory functions to avoid causing autoimmune reactions or injuring their own cells or tissues when fighting foreign cells. This set of regulatory functions, which we call immune checkpoint mechanisms, simply means that different groups of ligand and receptor reactions increase or inhibit the immune effects of T cells.. With years experience, Creative BioMart provides a wide range of immune checkpoint proteins and the bio-activity of all those products has been assayed and confirmed, making them essential materials for mechanistic studies and development of new therapeutics.. Creative BioMart immune checkpoint proteins mainly include: 2B4, 4-1BB, 4-1 BB Ligand, B7-1, ...
Immune checkpoints are one of the protective mechanisms in normal organisms. Under the initiation of the usual immune system, T cells can perform antigen-specific cytotoxicity and guide other immune responses against foreign organisms with antigens different from the host itself; however, such functions need to have a set of regulatory functions to avoid causing autoimmune reactions or injuring their own cells or tissues when fighting foreign cells. This set of regulatory functions, which we call immune checkpoint mechanisms, simply means that different groups of ligand and receptor reactions increase or inhibit the immune effects of T cells.. With years experience, Creative BioMart provides a wide range of immune checkpoint proteins and the bio-activity of all those products has been assayed and confirmed, making them essential materials for mechanistic studies and development of new therapeutics.. Creative BioMart immune checkpoint proteins mainly include: 2B4, 4-1BB, 4-1 BB Ligand, B7-1, ...
Immune checkpoints are one of the protective mechanisms in normal organisms. Under the initiation of the usual immune system, T cells can perform antigen-specific cytotoxicity and guide other immune responses against foreign organisms with antigens different from the host itself; however, such functions need to have a set of regulatory functions to avoid causing autoimmune reactions or injuring their own cells or tissues when fighting foreign cells. This set of regulatory functions, which we call immune checkpoint mechanisms, simply means that different groups of ligand and receptor reactions increase or inhibit the immune effects of T cells.. With years experience, Creative BioMart provides a wide range of immune checkpoint proteins and the bio-activity of all those products has been assayed and confirmed, making them essential materials for mechanistic studies and development of new therapeutics.. Creative BioMart immune checkpoint proteins mainly include: 2B4, 4-1BB, 4-1 BB Ligand, B7-1, ...
Results of the present study show for the first time that Chk1 undergoes activating phosphorylation in marrow blasts in vivo during cytarabine-containing induction therapy. Building on this result, we also show in human AML cell lines that the selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest, increases cytarabine-induced apoptosis, and enhances the effects of cytarabine on colony formation. Likewise, SCH 900776 increases the effects of cytarabine in a majority of primary AML isolates but not normal myeloid progenitors in vitro. This sensitization was observed at SCH 900776 concentrations far below the approximate 5 μmol/L SCH 900776 peak levels observed at the maximum tolerated dose in solid tumor patients. These observations have potentially important implications for current efforts to enhance the efficacy of cytarabine-containing AML regimens.. Previous results have shown that cytarabine activates the ATR/Chk1 checkpoint in tissue culture cell lines in vitro ...
Eukaryotic organisms use cell-cycle checkpoints to ensure that nuclear division is restrained while DNA is undergoing replication or repair. Recent studies of the fission yeast Schizosaccharomyces pombe have illuminated these checkpoint mechanisms. These investigations have connected checkpoint proteins with central elements of the mitotic-control machinery ...
Early studies in lower Eukaryotes have defined a role for the members of the NimA related kinase (Nek) family of protein kinases in cell cycle control. Expansion of the Nek family throughout evolution has been accompanied by their broader involvement in checkpoint regulation and cilia biology. Moreover, mutations of Nek family members have been identified as drivers behind the development of ciliopathies and cancer. Recent advances in studying the physiological roles of Nek family members utilizing mouse genetics and RNAi-mediated knockdown are revealing intricate associations of Nek family members with fundamental biological processes. Here, we aim to provide a comprehensive account of our understanding of Nek kinase biology and their involvement in cell cycle, checkpoint control and cancer.
In the laboratory, yeast is usually grown in the presence of high glucose, and lab yeast is adapted for those conditions. If strains more typical of wild yeast are maintained under conditions with few nutrients, they will show a synchronous cycle of alternating respiratory and glycolytic metabolism. Cell division is confined to the glycolytic (or reductive) phase. Chen et al. hypothesized that this occurs to prevent replication from taking place in an oxidizing environment, which could cause mutations. When cells were forced to divide during the oxidizing phase of the metabolic cycle by introducing one of several cell cycle mutations or treating with H2O2, an increased level of DNA mutation was indeed observed. In addition, a mutation in a DNA checkpoint kinase that links the cell and circadian cycles in other fungi disrupts cell synchrony, suggesting parallels between the metabolic and circadian cycles.. Z. Chen, E. A. Odstrcil, B. P. Tu, S. L. McKnight, Restriction of DNA replication to the ...
Press Release issued Jan 12, 2018: Cancer is the leading cause of death worldwide and hence offers a lot of unmet research areas yet to be targeted. The field of oncology is wide comprising a varied type of application area. The focus of researchers is gradually shifting towards the immunotherapies. The immunotherapy makes the use of bodys own components to fight cancer. Immune checkpoints are molecules that stimulate or inhibit the immune cells. Yervoy was the first drug launched in the immune checkpoint inhibitors domain. This anit-CTLA-4 drug was followed by many other drugs such as Keytruda and Opdivo. Besides these molecules there are several others under clinical development. There is an ongoing competition between the immune checkpoint inhibitors market contributors to emerge as a leader.
doc,The major effort in the lab is directed towards investigating how tumor-specific dysregulation of the pRB signaling pathway affects downstream gene expression and the cellular response to DNA damage. Four projects are currently underway. First, we are utilizing a modified chromatin immunoprecipitation approach to capture and identify genomic DNA target sequences conditionally associated with pRB-containing complexes recovered from intact chromatin in untransformed primary human cells. Second, we are investigating functional heterogeneity amongst closely related components in the pRB pathway. Specifically, we are conducting comparative analyses of the INK4 proteins p16INK4a and p18INK4c and their preferred target kinases, the cyclin dependent kinases cdk4 and cdk6. Third, in collaboration with Dr. Jeff Marks, we are developing a mammary gland organoid approach to quantitate and analyze parity-dependent DNA damage checkpoint responses in the context of the primary human mammary tissue. ...
"Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1". Oncogene. England. 22 (48): 7593-9. doi: ... "Synucleins are a novel class of substrates for G protein-coupled receptor kinases". J. Biol. Chem. 275 (34): 26515-22. doi: ... 13 (2): 95-103. doi:10.1006/mcne.1999.0735. PMID 10192768. Duda JE, Shah U, Arnold SE, et al. (2000). "The expression of alpha ... 5 (6): 401-2. doi:10.1093/dnares/5.6.401. PMID 10048491. Surguchov A, Surgucheva I, Solessio E, Baehr W (1999). "Synoretin--A ...
"Kinetochore localization and microtubule interaction of the human spindle checkpoint kinase Mps1". Chromosoma. 113 (1): 1-15. ... Chen Y, Riley DJ, Zheng L, Chen PL, Lee WH (Dec 2002). "Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is ... Chen Y, Riley DJ, Zheng L, Chen PL, Lee WH (Dec 2002). "Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is ... Martin-Lluesma S, Stucke VM, Nigg EA (Sep 2002). "Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of ...
"Kinetochore localization and microtubule interaction of the human spindle checkpoint kinase Mps1". Chromosoma. 113 (1): 1-15. ... 2004). "Nuf2 and Hec1 are required for retention of the checkpoint proteins Mad1 and Mad2 to kinetochores". Curr. Biol. 13 (23 ... Meraldi P, Draviam VM, Sorger PK (2004). "Timing and checkpoints in the regulation of mitotic progression". Dev. Cell. 7 (1): ... 2004). "Identification of the substrates and interaction proteins of aurora kinases from a protein-protein interaction model". ...
"Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1". Molecular and Cellular Biology. 20 ( ... "Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication ... 200 (1-2): 149-56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. Boddy MN, Lopez-Girona A, Shanahan P, Interthal H, Heyer WD ... 625 (1-2): 1-19. doi:10.1016/j.mrfmmm.2007.04.007. PMC 2100401 . PMID 17555773. Nomura Y, Adachi N, Koyama H (Oct 2007). "Human ...
"Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases". Proc. Natl. Acad. Sci. U.S.A. ... As a critical protein for cell division, MCM is also the target of various checkpoint pathways, such as the S-phase entry and S ... In late G1/early S phase, the pre-RC is activated for DNA unwinding by the cyclin-dependent kinases (CDKs) and DDK. This ... Upon entry into S phase, the activity of the CDKs and the Dbf4-dependent kinase (DDK) Cdc7 promotes the assembly of replication ...
Cayrol C, Cougoule C, Wright M (Nov 2002). "The beta2-adaptin clathrin adaptor interacts with the mitotic checkpoint kinase ... Cayrol C, Cougoule C, Wright M (Nov 2002). "The beta2-adaptin clathrin adaptor interacts with the mitotic checkpoint kinase ... AP-2 complex subunit beta is a protein that in humans is encoded by the AP2B1 gene. The protein encoded by this gene is one of ... 73 (2): 1350-61. PMC 103959 . PMID 9882340. Owen DJ, Vallis Y, Pearse BM, McMahon HT, Evans PR (Aug 2000). "The structure and ...
Pregueiro AM, Liu Q, Baker CL, Dunlap JC, Loros JJ (2006). "The Neurospora checkpoint kinase 2: a regulatory link between the ... and a calcium/calmodulin-dependent kinase (CAMK-1), and additional kinases, reaching its peak around mid-subjective day. Kinase ... FRQ recruits kinases such as casein kinase 1a (CK-1a) that phosphorylate WCC, although the function of these phosphorylations ... Additional interactions with other kinases including PRD-4 (CHK2) and casein kinase 2 (CKII) are known. Structural prediction ...
In eukaryotes, the cellular repair response to DNA damage is orchestrated, in part, by the DNA damage checkpoint kinase ATM. ... Waterworth WM, Footitt S, Bray CM, Finch-Savage WE, West CE (2016). "DNA damage checkpoint kinase ATM regulates germination and ... Praha). 47 (2): 50-4. PMID 11321247. Waterworth WM, Masnavi G, Bhardwaj RM, Jiang Q, Bray CM, West CE (2010). "A plant DNA ... 169 (2): 914-930. doi:10.1104/pp.15.00498. ISSN 1532-2548. PMC 4587445 . PMID 26276844. "A Sketch of an 8 Part Plant Hormone ...
The DNA damage checkpoint kinase ATM has a major role in integrating progression through germination with repair responses to ... Waterworth WM, Footitt S, Bray CM, Finch-Savage WE, West CE (2016). "DNA damage checkpoint kinase ATM regulates germination and ... Some seeds germinate when the soil is cool 28-40 F (-2 - 4 C), and some when the soil is warm 76-90 F (24-32 C). Some seeds ... Praha). 47 (2): 50-4. PMID 11321247. Waterworth WM, Masnavi G, Bhardwaj RM, Jiang Q, Bray CM, West CE (2010). "A plant DNA ...
The DNA checkpoint kinase ATM has a key role in integrating progression through germination with repair responses to the DNA ... Waterworth WM, Footitt S, Bray CM, Finch-Savage WE, West CE (2016). "DNA damage checkpoint kinase ATM regulates germination and ... 1995). "A receptor kinase-like protein encoded by the rice disease resistance gene, XA21". Science. 270 (5243): 1804-1806. doi: ... 2000). "FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis". ...
19] MPS1 is a protein kinase that is essential to the spindle assembly checkpoint, and may remodel an SAS6-cored intermediate ... "Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication". The EMBO Journal. 21 (7 ... This link between the cell cycle and the centrosome cycle is mediated by cyclin-dependent kinase 2 (Cdk2). There has been ample ... Phosphorylation is a key regulatory role in centrosome maturation and it is thought that Polo-like kinases (Plks) and Aurora ...
Stucke VM, Silljé HH, Arnaud L, Nigg EA (2002). "Human Mps1 kinase is required for the spindle assembly checkpoint but not for ... "Entrez Gene: TTK TTK protein kinase". Hanks SK, Quinn AM (1991). "Protein kinase catalytic domain sequence database: ... Dual specificity protein kinase TTK also known as Mps1 is an enzyme that in humans is encoded by the TTK gene. GRCh38: Ensembl ... 2003). "Human MPS1 Kinase Is Required for Mitotic Arrest Induced by the Loss of CENP-E from Kinetochores". Mol. Biol. Cell. 14 ...
... (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is ... Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH (Jan 1999). "A human homologue of the checkpoint kinase Cds1 ... The CHEK2 gene encodes for checkpoint kinase 2 (CHK2), a protein that acts a tumor suppressor. CHK2 regulates cell division, ... Cai Z, Chehab NH, Pavletich NP (Sep 2009). "Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase". ...
"Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex". The ... "Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 ... The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two ... A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several ...
"HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 ... Stage 2 (Moderate) Cannot work or maintain the more demanding aspects of daily life, but able to perform basic activities of ... 2 (6th ed.). Baltimore, MD: Williams and Wilkins. pp. 1644-1669. ISBN 0-683-04532-6. CS1 maint: Multiple names: authors list ( ... 1 (2): 230-6. doi:10.1016/j.stem.2007.07.010. PMID 18371353. Thomas, S; Mayer, L; Sperber, K (2009). "Mitochondria influence ...
Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene. This ... Posas F, Saito H (1998). "Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator". ... Chan GK, Jablonski SA, Sudakin V, Hittle JC, Yen TJ (1999). "Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E ... "p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase". Oncogene. 19 (40): ...
Yoshida K, Komatsu K, Wang HG, Kufe D (May 2002). "c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in ... "The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of ... Agami R, Shaul Y (April 1998). "The kinase activity of c-Abl but not v-Abl is potentiated by direct interaction with RFXI, a ... Cao C, Leng Y, Li C, Kufe D (April 2003). "Functional interaction between the c-Abl and Arg protein-tyrosine kinases in the ...
"Antitumor drug adozelesin differentially affects active and silent origins of DNA replication in yeast checkpoint kinase ...
Checkpoint kinases (Chks) are protein kinases that are involved in cell cycle control. Two checkpoint kinase subtypes have been ... Goto H, Izawa I, Li P, Inagaki M (Jul 2012). "Novel regulation of checkpoint kinase 1: Is checkpoint kinase 1 a good candidate ... Checkpoint kinase 1, commonly referred to as Chk1 is an Serine/threonine-specific protein kinase that in humans, is encoded by ... Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (Feb 2000). "The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) ...
The Tousled-like kinases, first described in Arabidopsis, are nuclear serine/threonine kinases that are potentially involved in ... and Chk1-dependent DNA damage checkpoint". The EMBO Journal. 22 (7): 1676-87. doi:10.1093/emboj/cdg151. PMC 152895 . PMID ... Serine/threonine-protein kinase tousled-like 1 is an enzyme that in humans is encoded by the TLK1 gene. ... Groth A, Lukas J, Nigg EA, Silljé HH, Wernstedt C, Bartek J, Hansen K (Apr 2003). "Human Tousled like kinases are targeted by ...
"Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints ... Jin J, Ang XL, Ye X, Livingstone M, Harper JW (Jul 2008). "Differential roles for checkpoint kinases in DNA damage-dependent ... Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ (Sep 1997). "Conservation of the Chk1 checkpoint ... Thus, this degradation represents one axis of a DNA damage checkpoint, complementing induction of p53 and p21 in the inhibition ...
"DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds". Proc. Natl. Acad. Sci. U.S.A. ... The DNA checkpoint kinase ATM has a key role in integrating progression through germination with repair responses to the DNA ... 2000). "FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis". ... 84 (2): 149-165. doi:10.5586/asbp.2015.020.. *^ a b Sánchez-Baracaldo, Patricia; Raven, John A.; Pisani, Davide; Knoll, Andrew ...
The PLK4 inhibitor R1530 down regulates the expression of mitotic checkpoint kinase BubR1 that in turn leads to polyploidy ... Serine/threonine-protein kinase PLK4 also known as polo-like kinase 4 is an enzyme that in humans is encoded by the PLK4 gene. ... "Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase". The Journal of Biological Chemistry. 276 (42): 39012- ... Li J, Tan M, Li L, Pamarthy D, Lawrence TS, Sun Y (April 2005). "SAK, a new polo-like kinase, is transcriptionally repressed by ...
"Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery". Current Biology. 16 (19): ... Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H (Mar 2004). "M-phase kinases induce phospho- ... Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H (Mar 2004). "M-phase kinases induce phospho- ... βTrCP plays important roles in regulating cell cycle checkpoints. In response to genotoxic stress, it contributes to turn off ...
de 2001). «Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase». Nature (England) 411 (6833): 102-7 ... de 1997). «Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase». Proc. Natl. Acad. Sci. ... de 1998). «RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen- ... de 1996). «Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade». J. ...
Lin HR, Ting NS, Qin J, Lee WH (Sep 2003). "M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the ... Meiotic recombination checkpoint. *RecF pathway. *DNA helicase: BLM. *WRN. *FANC proteins: core protein complex *FANCA ... doi:10.1016/s1097-2765(00)80276-2. PMID 9774970.. *^ Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, ... Table 2. Altered expression of microRNAs that affect RAD51 expression in sporadic cancers. MicroRNA. miRNA Over/Under ...
Checkpoint kinase 1 regulates diallyl trisulfide induced mitotic arrest in human prostate cancer cells. Anna Herman-Antosiewicz ... Checkpoint kinase 1 regulates diallyl trisulfide induced mitotic arrest in human prostate cancer cells ... Checkpoint kinase 1 regulates diallyl trisulfide induced mitotic arrest in human prostate cancer cells ... Checkpoint kinase 1 regulates diallyl trisulfide induced mitotic arrest in human prostate cancer cells ...
Previous Names: "CHK2 (checkpoint, S.pombe) homolog", "CHK2 checkpoint homolog (S. pombe)" ...
View mouse Chek2 Chr5:110839979-110874145 with: phenotypes, sequences, polymorphisms, proteins, references, function, expression
X-Ray Structures of Checkpoint Kinase 2 in Complex with Inhibitors that Target its Gatekeeper-Dependent Hydrophobic Pocket. ... Description: SERINE/THREONINE-PROTEIN KINASE CHK2 protein , Length: 323 No structure alignment results are available for 2YIQ.A ... 2] The all vs. all comparisons are based on jFATCAT (a Java port of the original FATCAT algorithm Yuzhen Ye & Adam Godzik (2003 ... Cov2: The coverage, or %, of aligned residues in chain 2. Table Info. The table is sorting is by P-value by default. Clicking ...
Activated Checkpoint Kinase 2 Expression and Risk for Oral Squamous Cell Carcinoma. Angela J. Yoon, Jing Shen, Regina M. ... Background: Phosphoactivation of a DNA damage response molecule checkpoint kinase 2 (pChk2) may be a marker of oral epithelial ... During the normal cellular response to DNA damage, the checkpoint kinase 2 (Chk2) protein is phosphorylated at threonine ... Activated Checkpoint Kinase 2 Expression and Risk for Oral Squamous Cell Carcinoma ...
The Neurospora Checkpoint Kinase 2: A Regulatory Link Between the Circadian and Cell Cycles ... The Neurospora Checkpoint Kinase 2: A Regulatory Link Between the Circadian and Cell Cycles ... The Neurospora Checkpoint Kinase 2: A Regulatory Link Between the Circadian and Cell Cycles ... The Neurospora Checkpoint Kinase 2: A Regulatory Link Between the Circadian and Cell Cycles ...
X-Ray Structures of Checkpoint Kinase 2 in Complex with Inhibitors that Target its Gatekeeper-Dependent Hydrophobic Pocket. ... Structural analysis of checkpoint kinase 2 in complex with PV1162, a novel inhibitor. ... SERINE/THREONINE-PROTEIN KINASE CHK2 protein, length: 323 (BLAST) Sequence Similarity Cutoff. Rank. Chains in Cluster. Cluster ... You can also use the structure comparison tool to compare any 2 given structures. ...
Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor ... Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor ... Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor ... Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor ...
Checkpoint kinase 2 and androgen receptor cross-talk regulate the DDR and prostate cancer growth. Huy Q Ta, Rosalie Sleppy, ... Checkpoint kinase 2 (CHK2) is a serine/threonine protein kinase whose main function is regulating the DNA damage response (DDR ... Checkpoint kinase 2 and androgen receptor cross-talk regulate the DDR and prostate cancer growth (. ... The binding of CHK2 with AR can be disrupted with CHK2 kinase inhibitors suggesting that the kinase activity of CHK2 is ...
Activation of Checkpoint Kinase 2 Is Critical for Herpes Simplex Virus Type 1 Replication in Corneal Epithelium ... Herpes simplex virus type 1 Keratitis Checkpoint kinase 2 Corneal epithelium Explant cornea DNA damage response Small-molecule ... This report examines the role of checkpoint kinase 2 (Chk2), a DDR mediator protein, in corneal epithelial HSV-1 infection. ,b ... Supplementary Material for: Activation of Checkpoint Kinase 2 Is Critical for Herpes Simplex Virus Type 1 Replication in ...
The compound also targets Aurora A kinase and tubulin in vitro and in cells, which can explain the observed spindle anomalies. ... The reduced activity of Aurora B kinase resulted in polyploidy and suppression of cancer cell viability. Our data suggest that ... One potential drug target within the mitotic machinery is the spindle assembly checkpoint (SAC), an evolutionarily conserved ... One potential drug target within the mitotic machinery is the spindle assembly checkpoint (SAC), an evolutionarily conserved ...
Category: Checkpoint Kinase Published November 4, 2018 Background/Purpose Transforming growth issue triggered kinase 1 (TAK1) ... Background/Purpose Transforming growth issue triggered kinase 1 (TAK1) is usually an integral MAPKKK family protein in ... Continue reading Background/Purpose Transforming growth issue triggered kinase 1 (TAK1) is usually an ... Changed expression of Bcl-2 family proteins performs central roles in apoptosis dysregulation in cancer and leukemia, promoting ...
Central to this network are protein kinases of the PIKK (phosphoinositide 3-kinase-related protein kinase) family, like ATM ( ... 1996 rad-dependent response of the chk1-encoded protein kinase at the DNA damage checkpoint. Science 271: 353-356. ... Activation of Checkpoint Kinase Chk1 by Reactive Oxygen Species Resulting from Disruption of wat1/pop3 in Schizosaccharomyces ... Activation of Checkpoint Kinase Chk1 by Reactive Oxygen Species Resulting from Disruption of wat1/pop3 in Schizosaccharomyces ...
X-Ray Structures of Checkpoint Kinase 2 in Complex with Inhibitors that Target its Gatekeeper-Dependent Hydrophobic Pocket. ... Structural analysis of checkpoint kinase 2 in complex with inhibitor PV1322. Display Files *FASTA Sequence ...
... Breast cancer. Prostate cancer. Li-Fraumeni /Li-Fraumeni-like Syndrome. ... CHEK2 encodes a Serine/threonine-protein kinase which plays a critical role in DNA damage signaling pathways1. CHEK2 directly ... phosphorylates and regulates the functions of p53 and BRCA1 2,3. Most women with breast and/or ovarian cancer are not carriers ...
In mammalian cells, four protein kinases form the PI3-kinase-related protein kinase (PIK) superfamily. These four enzymes-FRAP ... and their sequence similarity to the p110 lipid kinase subunit of PI3-kinase. FRAP (FKBP12 and rapamycin-binding protein kinase ... Responses to DNA damage and regulation of cell cycle checkpoints by the ATM protein kinase family.. Hoekstra MF1. ... Recent studies in this protein kinase family indicate an important role for ATM and ATR in a meiotic surveillance mechanism ...
Mitotic kinases as regulators of cell division and its checkpoints.. Nigg EA1. ... Here, I give an overview of the many mitotic kinases that regulate cell division and the fidelity of chromosome transmission. ...
The meiotic roles of the canonical checkpoint kinases Bub1, Mps1, the pseudokinase BubR1 (Mad3), and Aurora B and C (Ipl1) will ... The signaling cascade leading to checkpoint arrest depends on several protein kinases that are conserved from yeast to man. In ... The signaling cascade leading to checkpoint arrest depends on several protein kinases that are conserved from yeast to man. In ... The meiotic roles of the canonical checkpoint kinases Bub1, Mps1... ...
Mitotic checkpoint serine/threonine-protein kinase BUB1Imported. ,p>Information which has been imported from another database ... tr,C9JQA4,C9JQA4_HUMAN Mitotic checkpoint serine/threonine-protein kinase BUB1 (Fragment) OS=Homo sapiens GN=BUB1 PE=1 SV=1 ... 2 - 146. BUB1 N-terminalInterPro annotation. ,p>Information which has been generated by the UniProtKB automatic annotation ...
Abbreviations: CHEK2, checkpoint kinase 2; SCD: N-terminal SQ/TQ cluster domain; FHA, forkhead-associated domain; NR: not ... When double-stranded DNA is damaged, checkpoint kinase 2 (CHEK2) is phosphorylated, which in turn phosphorylates its downstream ... When double-stranded DNA is damaged, checkpoint kinase 2 (CHEK2) is phosphorylated, which in turn phosphorylates its downstream ... Y390C mutation occurs in the serine/threonine kinase domain,[26] which disrupts the kinase function of CHEK2 and prevents the ...
The mitotic spindle checkpoint, which is regulated by Aurora B kinase, ensures proper kinetochore attachment to chromosomes ... MAP kinase regulation of the mitotic spindle checkpoint.. Eves EM1, Rosner MR. ... One mechanism by which the fidelity of this process is guaranteed is through the activation of cell cycle checkpoints. ... As demonstrated by immunofluorescence at kinetochores, depletion of Raf Kinase Inhibitory Protein (RKIP), an inhibitor of Raf/ ...
Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors. ... Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors ... Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors ... Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors ...
A. J. Yoon, J. Shen, H. C. Wu et al., "Expression of activated checkpoint kinase 2 and histone 2AX in exfoliative oral cells ... A. J. Yoon, J. Shen, R. M. Santella, D. J. Zegarelli, R. Chen, and I. B. Weinstein, "Activated checkpoint kinase 2 expression ... T. H. Stracker, T. Usui, and J. H. J. Petrini, "Taking the time to make important decisions: the checkpoint effector kinases ... DDR is mediated by a signal transduction cascade involving the ataxia telangiectasia mutated (ATM-) check point kinase 2 (Chk2 ...
We report that CK2 is essential for porcine oocyte meiotic maturation by regulating spindle assembly checkpoint (SAC). ... is a serine/threonine-selective protein kinase that has been involved in a variety of cellular processes such as DNA repair, ... Modulation of human checkpoint kinase Chk1 by the regulatory beta-subunit of protein kinase CK2. Oncogene. 2003;22(32):4933-42. ... Lebrin F, Chambaz EM, Bianchini L. A role for protein kinase CK2 in cell proliferation: evidence using a kinase-inactive mutant ...
Kinase Enzyme System. CHK2 Kinase Enzyme System. Official Name. checkpoint kinase 2 ... Kinase Enzyme System. TAK1-TAB1 Kinase Enzyme System. Official Name. TAK1: mitogen-activated protein kinase kinase kinase 7. ... Kinase Enzyme System. MAPKAPK2 Kinase Enzyme System. Official Name. mitogen-activated protein kinase-activated protein kinase 2 ... Kinase Enzyme System. MAPKAPK3 Kinase Enzyme System. Official Name. mitogen-activated protein kinase-activated protein kinase 3 ...
  • CHEK2 encodes a Serine/threonine-protein kinase which plays a critical role in DNA damage signaling pathways 1 . (cityofhope.org)
  • CHEK2 has 3 functional domains, namely, N-terminal SQ/TQ cluster domain (SCD), central forkhead-associated (FHA) domain, and C-terminal serine/threonine-kinase domain (KD), each of which has specific functions. (medscape.com)
  • Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors. (cdc.gov)
  • Partial sequences of exon 10 and exon 2 of CHEK2. (nih.gov)
  • Two more CHEK2 gene mutations, CHEK2*S428F, an amino-acid substitution to the kinase domain in exon 11 and CHEK2*P85L, an amino-acid substitution in the N-terminal region (exon 1) have been found in the Ashkenazi Jewish population. (wikipedia.org)
  • CK2 (casein kinase 2) is an ubiquitously expressed and highly conserved serine/threonine protein kinase that forms a tetramer containing two catalytic (α and/or α´) subunits and two regulatory β subunits [ 1 ]. (biomedcentral.com)
  • Similarly to its role in kinetochore assembly, it recruits members of the chromosomal passenger complex (CPC) like Aurora B kinase, Survivin and INCENP. (wikipedia.org)
  • Similarly, overexpression of polo-like kinases, such as PLK1 and PLK2 , have also been shown to correlate with prognosis, histologic grade, and clinical stage in ovarian cancer ( 14-16 ). (aacrjournals.org)
  • Plk1 function may be important for relieving the inhibitory checkpoint signal. (wikipedia.org)
  • A) In vitro kinase assay was performed by recombinant Rph1 or BSA incubated with or without V5-IP WT or KD Rad53 supplied by γ32P-ATP. (nih.gov)
  • To test whether Rph1 is a substrate of Rad53, we performed an in vitro kinase assay by incubating IP-activated Rad53 (WT or KD) with recombinant Rph1. (nih.gov)