• Inhibition of the FEN1 repair protein with small molecule inhibitors was observed to preferentially kill cancer cell lines that were already deficient in expression of BRCA1 and BRCA2 proteins. (wikipedia.org)
  • Although the senescent cells remain viable, they show typical changes with enlarged and flattened cell bodies, apoptosis resistance, increased activity of senescence-associated β -galactosidase (SA- β -gal), and upregulation of cyclin-dependent kinase (CDK) inhibitors including p16 INK4A , ARF proteins, and p21 [ 13 - 16 ]. (hindawi.com)
  • We show that cyclin-dependent kinase (CDK) consensus motifs are frequently clustered in CDK substrate proteins. (biomedcentral.com)
  • The activity of CDKs is controlled by their binding to coactivator subunits termed Cyclins, as well as by CDK inhibitory proteins termed CKIs. (intechopen.com)
  • The accumulation of both Cyclin and CKI proteins is tightly regulated at the level of transcription. (intechopen.com)
  • In addition, Cyclin and CKI proteins are controlled at the level of their destruction. (intechopen.com)
  • Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, may have functions beyond that of cell cycle regulation. (biomedcentral.com)
  • Protein kinases, the enzymes responsible for protein phosphorylation, make up almost 2% of protein-encoding genes in the human genome [ 1 ] and an estimated 30-50% of human proteins are phosphorylated [ 2 ]. (biomedcentral.com)
  • Protein kinases and their substrates regulate essentially all cellular processes through complex regulatory networks, in which phosphorylated proteins act as switches that tune the response of the cell to environmental stimuli. (biomedcentral.com)
  • A large family of regulatory proteins that function as accessory subunits to a variety of CYCLIN-DEPENDENT KINASES. (umassmed.edu)
  • Two proteins have been implicated in expression-independent vitamin D action: membrane VDR and the membrane-associated rapid response steroid binding (1,25D 3 -MARRS) protein. (biomedcentral.com)
  • E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. (e3ligasesignal.com)
  • Here we compare the specificity of two budding yeast cyclins, the S-phase cyclin Clb5 and the M-phase cyclin Clb2, in the phosphorylation of 150 Cdk1 (Cdc28) substrates. (nature.com)
  • Although we did not identify any highly Clb2-specific substrates, we found that Clb2-Cdk1 possessed higher intrinsic kinase activity than Clb5-Cdk1, enabling efficient phosphorylation of a broad range of mitotic Cdk1 targets. (nature.com)
  • Furthermore, both robust phosphorylation of Homer3 and its dissociation from metabotropic glutamate receptor 1α (mGluR1α) were triggered by depolarization in primary cultured Purkinje cells, and these events were inhibited by CaMKII inhibitor. (jneurosci.org)
  • An in vitro binding kinetic analysis revealed that these phosphorylation-dependent events were attributable to a decrease in the affinity of phosphorylated Homer3 for its ligand. (jneurosci.org)
  • In this study, we revealed that Homer3 was phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) in Purkinje cells, and the phosphorylation reduces the affinity for Homer target molecules, resulting in change of the solubility. (jneurosci.org)
  • The method, named Predikin, identifies key conserved substrate-determining residues in the kinase catalytic domain that contact the substrate in the region of the phosphorylation site and so determine the sequence surrounding the phosphorylation site. (biomedcentral.com)
  • Predikin now consists of two components: (i) PredikinDB, a database of phosphorylation sites that links substrates to kinase sequences and (ii) a Perl module, which provides methods to classify protein kinases, reliably identify substrate-determining residues, generate scoring matrices and score putative phosphorylation sites in query sequences. (biomedcentral.com)
  • New features in Predikin include the use of SQL queries to PredikinDB to generate predictions, scoring of predictions, more reliable identification of substrate-determining residues and putative phosphorylation sites, extended options to handle protein kinase and substrate data and an improved web interface. (biomedcentral.com)
  • Cla4-dependent phosphorylation is required for the ubiquitylation and subsequent degradation of Vac17 and the release of the vacuole from Myo2. (rupress.org)
  • Bhaduri S, Valk E, Winters MJ, Gruessner B, Loog M, Pryciak PM. A docking interface in the cyclin Cln2 promotes multi-site phosphorylation of substrates and timely cell-cycle entry. (umassmed.edu)
  • As a universal inhibitor of cyclin-dependent kinases and one of the target genes of the tumor suppresser p53, p21Waf1/Cip1 can act as a tumor suppresser through its ability to control cell cycle progression. (ox.ac.uk)
  • Finally, epitope mapping of the anti-p21Waf1/Cip1 antibodies using a peptide library covering the entire p21Waf1/Cip1 protein sequence indicates that two of the antibodies recognize a region of p21Waf1/Cip1 close to that bound by proliferating cell nuclear antigen. (ox.ac.uk)
  • HDAC inhibition resulted in a transcriptional and posttranscriptional regulation of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip). (cret-signal.com)
  • Miller, M. E. & Cross, F. R. Cyclin specificity: how many wheels do you need on a unicycle? (nature.com)
  • A- and B-type cyclins differentially modulate substrate specificity of cyclin-cdk complexes. (nature.com)
  • Brown, N. R., Noble, M. E., Endicott, J. A. & Johnson, L. N. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. (nature.com)
  • Signaling specificity is conferred by receptors and mediated through associated-kinases. (janechin.net)
  • We have previously described an approach to predicting the substrate specificity of serine-threonine protein kinases. (biomedcentral.com)
  • The second factor, termed peptide specificity, describes the interaction between amino acid residues in the catalytic domain of the protein kinase and the substrate residues that surround the phosphorylated residue. (biomedcentral.com)
  • The relative contribution of substrate recruitment and peptide specificity to protein kinase substrate specificity varies between protein kinases. (biomedcentral.com)
  • However, it is recognised that for many protein kinase families, particularly those that phosphorylate Ser/Thr residues, peptide specificity is the major factor that determines substrate specificity. (biomedcentral.com)
  • The prediction of peptide specificity is therefore the basis for most of the available computational methods aimed at predicting substrates of protein kinases. (biomedcentral.com)
  • F-box protein specificity for g1 cyclins is dictated by subcellular localization. (umassmed.edu)
  • Crystal structures of protein kinases with bound substrate peptides show that substrate residues at positions -3 to +3 relative to the phosphorylated serine, threonine or tyrosine residue adopt an extended conformation and bind to a pocket in the catalytic domain of the protein kinase [ 8 ]. (biomedcentral.com)
  • Protein kinases are critical to cellular signalling and post-translational gene regulation, but their biological substrates are difficult to identify. (biomedcentral.com)
  • The new features significantly enhance the ability of Predikin to analyse protein kinases and their substrates. (biomedcentral.com)
  • In general, a protein kinase acts on a discrete set of substrates to ensure that signalling fidelity is maintained. (biomedcentral.com)
  • In addition, TRO can cause an induction of Cu 2+ /Zn 2+ -superoxide dismutase (CuZnSOD) [ 20 , 21 ] and the activated receptor complexes of TRO can induce catalase through binding to its promoter region [ 22 , 23 ]. (e-roj.org)
  • Transcriptional and translational control, sequestration in cyclin D1 complexes and localization all regulate p27 in G1 phase. (biomedcentral.com)
  • The stable association of Vpu with βTrCP also affects the latter's cellular functions, one of which is to direct the proteosomal degradation of inhibitor of kappa B (IκB) [ 14 ]. (biomedcentral.com)
  • Like the endogenous HPK1, both wild-type HPK1 and its kinase-dead mutant, HPK1-M46, overexpressed in Panc-1 cells, were also targeted by proteasome-mediated degradation. (aacrjournals.org)
  • Schulman, B. A., Lindstrom, D. L. & Harlow, E. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. (nature.com)
  • Finally, we examine co-clustering of the CDK consensus motifs with the 'cy' or RXL motif [ 17 ], which is known to be important in determining which CDK-cyclin complex will phosphorylate a given substrate. (biomedcentral.com)
  • How a particular protein kinase recognises its substrate protein(s) is therefore a key question. (biomedcentral.com)
  • Two major factors determine the formation of a protein kinase-substrate complex [ 4 ]. (biomedcentral.com)
  • The first, termed substrate recruitment, encompasses any process that increases the effective concentration of the protein kinase substrate. (biomedcentral.com)
  • The heptapeptide sequence from -3 to +3 that best binds to the pocket is determined by the physicochemical nature of the residues in the catalytic domain that line the pocket and contact the substrate. (biomedcentral.com)
  • Pope PA, Bhaduri S, Pryciak PM. Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1. (umassmed.edu)
  • PTEN encodes a protein kinase of the same name and functions as a tumor suppressor through regulation of cell proliferation. (medscape.com)
  • Mice lacking the tumor suppressors p16(Ink4a) (Cdkn2a, cyclin-dependent kinase inhibitor 2a), p19(Arf) (an alternative reading frame product of Cdkn2a,), and p27(Kip1) (Cdkn1b, cyclin-dependent kinase inhibitor 1b) result in malignant progression of epithelial cancers, sarcomas, and melanomas, respectively. (koreamed.org)
  • Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. (smpdb.ca)
  • p21 and other tumor suppressor genes' inactivation are therefore most likely involved in the first steps of the cancer model, with later stages possibly involving protooncogene activation and inflammation. (medscape.com)
  • p27(Kip1) is a cyclin-dependent kinase inhibitor. (biomedcentral.com)
  • The cyclin-dependent kinase (CDK) inhibitor p27(Kip1) is a key cell-cycle regulator of G1-to-S phase transition [ 1 ]. (biomedcentral.com)
  • Vincristine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. (smpdb.ca)
  • Growth factors that signal through tyrosine-kinase receptor families include the epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and transforming-growth factor-α (TGF-α). (janechin.net)
  • Our study reveals a critical step in the spatial regulation of myosin V-dependent organelle transport and may reveal common mechanisms for how molecular motors accurately deposit cargoes at the correct locations. (rupress.org)
  • This growth inhibition by TRO is linked to the G1 phase cell cycle arrest through the up-regulation of the cyclin-dependent kinase inhibitors p21 and p27 [ 14 - 16 ] and/or repression of cyclin D1 expression [ 17 , 18 ]. (e-roj.org)
  • Up-regulation appears to be specific to p27 because expression of cyclin D1, E, and A, and p21Cip1/Waf1 was not modulated by these agents. (biomedcentral.com)
  • Up-regulation of the expression of p27 is likely due to the activation of translation rather than transcription of p27 because (a) up-regulation is mediated by the 5'-untranslated region (-575) of the p27 gene and (b) the antibiotic actinomycin D, an inhibitor of transcription, did not attenuate the up-regulation of p27. (biomedcentral.com)
  • A schematic of the Cdkn2a locus with TALEN-binding nucleotides (blue) and the amino acid sequences (purple) of the WT (upper) and KO (lower) mice are shown. (koreamed.org)
  • Bandyopadhyay S, Bhaduri S, ?rd M, Davey NE, Loog M, Pryciak PM. Comprehensive Analysis of G1 Cyclin Docking Motif Sequences that Control CDK Regulatory Potency In?Vivo. (umassmed.edu)
  • The 3′UTR luciferase reporter assay confirmed that miR-183 directly regulated PDCD4 by binding to sequences in the 3′UTR of PDCD4. (molcells.org)
  • Transforming growth factor-β1 (TGF-β) signals through a serine/threonine-kinase receptor pathway. (janechin.net)
  • By the treatment of CDK4 inhibitor, the induction or the maintenance of Long-term potentiation (LTP) in response to a strong tetanus and NMDA receptor-dependent long-term depression (LTD) were normal in hippocampus. (biomedcentral.com)
  • Gonadotropin releasing hormone (GnRH), both types I and II, is a decapeptide hormone that stimulates the release of gonadotropin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary through specific binding to the GnRH receptor located on the external membrane of selected cell types [ 1-3 ]. (annexpublishers.co)
  • b) 4-Hydroxytamoxifen (but not tamoxifen), genistein (but not genistin), daidzein, and probably other nutritional and chemopreventive anti-cancer agents could up-regulate expression of p27 via receptor protein tyrosine kinases (RPTKs), phosphoinositide 3-kinase (PI3K), phosphoinosite-dependent kinase (PDK), Akt/PKB and mTOR. (biomedcentral.com)
  • Vitamin D is a steroid hormone that exerts most of its biological activities by binding to a specific high-affinity receptor, the vitamin D receptor (VDR). (biomedcentral.com)
  • Somatostatin , peptide with 14 amino acids, 3 mg per day, injected slowly in the evening after supper, subcutaneously or intravenously with a 12-hour timed syringe (evening administration is indispensable since this coincides with the nocturnal peak in GH and GH-dependent growth factors). (beatingcancercenter.com)
  • This results in inhibition of NFκB activity and the NFκB-dependent expression of anti-apoptotic genes of the Bcl-2 family [ 15 ]. (biomedcentral.com)
  • Finally, we provide evidence that these observations are applicable in vivo by demonstrating that HDAC inhibition decreased neointima formation and expression of cyclin D1 in a murine model of vascular injury. (cret-signal.com)
  • It further inhibited cell-cycle progression in the G1 phase by four different mechanisms: rapid downregulation of cyclin D1, induction of Chk2 with simultaneous downregulation of Cdc25A, induction of the Cdk-inhibitor p21 Cip/Waf and inhibition of ribonucleotide reductase activity resulting in reduced dCTP and dTTP levels. (nature.com)
  • A number of kinases were identified by sequence analysis that could potentially phosphorylate E1 at the identified positions. (biomedcentral.com)
  • Fisher, D. L. & Nurse, P. A single fission yeast mitotic cyclin B p34 cdc2 kinase promotes both S-phase and mitosis in the absence of G1 cyclins. (nature.com)
  • Donaldson, A. D. The yeast mitotic cyclin Clb2 cannot substitute for S phase cyclins in replication origin firing. (nature.com)
  • FEN1 is an essential enzyme in an inaccurate pathway for repair of double-strand breaks in DNA called microhomology-dependent alternative end joining or microhomology-mediated end joining (MMEJ). (wikipedia.org)
  • Growth factors do not only stimulate cell proliferation, but they may also act as growth inhibitors, depending on the cell type and the stimulatory pathway that is involved. (biomedcentral.com)
  • Increased sub-G1 population and annexin-V binding, activation of caspases 9 and 3, cleavage of poly(ADPribose) polymerase (PARP), and a decrease of mitochondrial membrane potential (MMP) indicated involvement of the mitochondrial apoptotic pathway in terpinen-4-ol-treated A549 and CL1-0 cells. (hindawi.com)
  • Our results indicated that terpinen-4-ol induced apoptosis through a mitochondria-mediated pathway in NSCLC cells and that the apoptosis elicited by terpinen-4-ol was p53 dependent. (hindawi.com)
  • Exploring the role of insulin-like growth factor binding protein-1 in identifying idiopathic multicentric Castleman's disease types: Implications for the mTOR signaling pathway. (harvard.edu)
  • Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. (aacrjournals.org)
  • They further link to the activation of protein kinase C- (PKC-) induced generation of reactive oxygen species (ROS) [ 6 , 7 ], which further mediates the activation of downstream transcription factor nuclear factor kappa-light-chain enhancer of activated B cells (NF- κ B). Thus, the main treatments of DN refer to modulate glycemic and blood pressure through insulin and RAS inhibitors. (hindawi.com)
  • These pericryptal myofibroblasts produce the Wnt signalling ligands which bind to Frizzled receptors as well as morphogenetic protein (BMP) antagonists gremlin 1(GREM1), gremlin 2 (GREM2) on basal epithelial stem cells and also can modulate notch signaling. (biomedcentral.com)
  • Our results indicated that terpinen-4-ol elicited a dose-dependent cytotoxic effect, as determined by MTT assay. (hindawi.com)
  • To be able stabilizing the kinetics of microtule, vincristine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. (smpdb.ca)
  • Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. (bace-signal.com)
  • Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor. (harvard.edu)
  • Putative target residues can be predicted by searching for matches to the consensus for a particular kinase. (biomedcentral.com)
  • We also aimed to evaluate the expression of TGF-β1 and p27 in the context of other cell cycle and proliferation markers such as cyclin D1 and Ki-67. (biomedcentral.com)
  • It has also been demonstrated that TGF-β induced cell cycle arrest can be partially attributed to the regulatory effects of TGF-β on both the expression and activity of cyclin-dependent kinase inhibitors [CDKI] such as p21 and p27. (biomedcentral.com)
  • Mutations in cyclin-dependent kinase inhibitors controlling the G1 phase of the cell cycle are prevalent in various cancers. (koreamed.org)
  • The outcome of this decision-making process is cell state dependent and, consequently, requires the integration of vast amounts of information that is encoded in the local abundance and functional state of a multitude of biomolecules acting as cell state sensors and transmitters. (biomedcentral.com)
  • Recent reports have indicated that terpinen-4-ol exerts its antitumor effects by triggering caspase-dependent apoptosis in human melanoma cells or by inducing necrotic cell death and cell-cycle arrest in mouse mesothelioma and melanoma cell lines without affecting normal cells [ 14 , 15 ]. (hindawi.com)
  • The cell division process is dependent on a tightly controlled sequence of events. (cancerquest.org)
  • As shown below, binding of the growth factor can lead to cell division. (cancerquest.org)
  • Several of these kinases have known roles in regulating cell cycle progression. (biomedcentral.com)
  • An infection is established in the basal layer of the epithelium, and a complex viral life cycle is carried out, dependent on the differentiation state of the host cell [ 1 - 3 ]. (biomedcentral.com)
  • Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. (umassmed.edu)
  • Hypoxia and genetic defects that chronically drive proliferation leave such tumors dependent on a steady supply of nutrients, especially glucose. (springer.com)
  • Here we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. (bace-signal.com)
  • A serine threonine kinase that controls a wide range of growth-related cellular processes. (harvard.edu)
  • Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. (smpdb.ca)
  • The protein is referred to as the target of RAPAMYCIN due to the discovery that TACROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity. (harvard.edu)
  • cyclin D1 mRNA expression and cyclin D1 promoter activity. (cret-signal.com)
  • Treatment of Panc-1 cells with a proteasome inhibitor, MG132, increased the HPK1 protein levels in a dose-dependent manner, suggesting that alteration in proteasome activity contributes to the loss of HPK1 protein expression in pancreatic cancer. (aacrjournals.org)
  • Histone deacetylation was essential during a specific temporal window of development and was dependent on the enzymatic activity of histone deacetylases, whose expression was detected in the developing corpus callosum. (rupress.org)
  • During the first 10 postnatal days, administration of valproic acid (VPA), the specific inhibitor for histone deacetylase activity, resulted in significant hypomyelination with delayed expression of late differentiation markers and retained expression of progenitor markers. (rupress.org)
  • Digalloyl-resveratrol (di-GA) is a synthetic compound aimed to combine the biological effects of the plant polyhydroxy phenols gallic acid and resveratrol, which are both radical scavengers and cyclooxygenase inhibitors exhibiting anticancer activity. (nature.com)
  • Precis: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a pro-apoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. (bace-signal.com)
  • Protein kinases are ubiquitous components of cellular signalling networks [ 1 ]. (biomedcentral.com)
  • After MG132 withdrawal, wild-type HPK1 protein expression was markedly decreased within 24 hours, but kinase-dead HPK1 mutant protein expression was sustained for up to 96 hours. (aacrjournals.org)
  • The change of radiation sensitivity by combined with TRO is not dependent on the PPARγ expression level. (e-roj.org)
  • We found that Homer3, the predominant isoform in Purkinje cells, is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) both in vitro and in vivo . (jneurosci.org)
  • These events are dependent on the proper levels of transcription and translation of certain genes. (cancerquest.org)
  • Our results indicated that the activation of cyclinD1-CDK4 is required for short-term synaptic plasticity and mGluR-dependent LTD, and suggested that this cyclin-dependent kinase may have different roles during the postnatal development in mice hippocampus area CA1. (biomedcentral.com)
  • Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. (bace-signal.com)
  • Mass spectrometry and in silico sequence analysis were used to identify phosphate sites on the BPV E1 protein and kinases that may recognize these sites. (biomedcentral.com)
  • Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer. (harvard.edu)
  • Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer. (harvard.edu)