• CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. (wikipedia.org)
  • The protein consists of 543 amino acids and the following domains: N-terminal SQ/TQ cluster domain (SCD) Central forkhead-associated (FHA) domain C-terminal serine/threonine kinase domain (KD) The SCD domain contains multiple SQ/TQ motifs that serve as sites for phosphorylation in response to DNA damage. (wikipedia.org)
  • Specifically, DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2. (wikipedia.org)
  • In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. (nature.com)
  • In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 tumor suppressor protein. (kegg.jp)
  • Another important pathway is the AMP-activated protein kinase (AMPK) pathway. (sigmaaldrich.com)
  • The presence of replication stress activates the DNA damage response and downstream checkpoint proteins including ataxia telangiectasia and Rad3 related kinase (ATR), checkpoint kinase 1 (CHK1), and WEE1-like protein kinase (WEE1), which trigger cell cycle arrest while protecting and restoring stalled replication forks. (bmj.com)
  • Chk1 is a checkpoint kinase activated during genotoxic stress. (reactome.org)
  • Analogous to the Chk1 kinase existing downstream of ATR, the Chk2 checkpoint kinase is modified and activated by ATM. (reactome.org)
  • Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. (reactome.org)
  • Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. (idrblab.net)
  • Whereas the different DNA repair pathways and the proteins they involve are know pretty well described, how they are regulated relative to each other in time and space remains to be deciphered. (cea.fr)
  • It seems now clear that posttranslational modification of both DNA repair and checkpoint proteins is of importance for the regulation of their activities but how these modifications are regulated and how they affect the activity of the proteins only begins to be described. (cea.fr)
  • This is accompanied by DNA double-strand break (DSB) induction and recruitment of the DNA repair proteins replication protein A, Rad51, and 53BP1 to damaged regions. (rupress.org)
  • This family of proteins contribute Bis-NH2-C1-PEG3 to cellular disintegration via targeted cleavage of a collection of proteins involved in many processes within the cell, including DNA repair and checkpoint Bis-NH2-C1-PEG3 activation (2). (cancercurehere.com)
  • J-H Lee et al also have provided the first evidence showing that PIG3 is closely associated with the induction and maintenance of the phosphorylation of H2AX and some other DDR proteins after DNA damage induced by NCS ( 8 ). (ijbs.com)
  • We have reported that many insults can trigger cells to activate a cellular death pathway (Nature, 361:739-742, 1993), that several viruses encode proteins to block attempted cell suicide (Proc. (hopkinsmedicine.org)
  • and the intrinsic pathway, which is activated by cellular stress and is regulated primarily at the level of mitochondria by the Bcl-2 family of proteins ( Fig. 1 ). (biologists.com)
  • The intrinsic apoptotic pathway is initiated in response to a variety of stress signals ( Willis and Adams, 2005 ), and a complex interplay of Bcl-2 proteins relays this signal to the mitochondrial outer membrane (OM) to initiate Bak and Bax activation, oligomerisation and OM damage ( Fig. 1 ). (biologists.com)
  • Once activated, CHK2 phosphorylates downstream targets including CDC25 phosphatases, responsible for dephosphorylating and activating the cyclin-dependent kinases (CDKs). (wikipedia.org)
  • Change in localisation depends on the checkpoint kinases Tel1ATM and Mec1ATR and has a positive effect on spontaneous recombination. (cea.fr)
  • Current insight revealed aerobic glycolysis supports various biosynthetic pathways and, consequently, the metabolic requirements for proliferation. (sigmaaldrich.com)
  • AMPK is often considered a metabolic checkpoint as it can control cell proliferation when activated under energetic stress, and activation of AMKP results in the inhibition of mTOR activity. (sigmaaldrich.com)
  • Indeed, it has been shown that miRNAs play an important role in gene expression, mainly when associated with the monitoring of several cell and metabolic pathways, being also an essential component of the gene silencing machinery in most eukaryotic organisms ( 4 , 8 ). (frontiersin.org)
  • Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. (springer.com)
  • In the presence of errors or damage during DNA replication, cell cycle checkpoint nodes and repair machinery work in concert to retard cell cycle progression until sufficient repair has been achieved. (bmj.com)
  • The repair of DNA damage involves a highly coordinated series of events: first, the cell must signal to halt cell cycle progression at precise cell cycle checkpoints, following this, DNA damage-specific repair pathways are activated (1). (cancercurehere.com)
  • miRNAs expressed in a wide variety of human cancers can regulate posttranscriptional gene expression by binding to the 3′ untranslated region of the target mRNAs and act as oncogenes or tumor suppressors to regulate cell signaling pathways, affecting tumorigenesis and tumor progression [ 17 ]. (hindawi.com)
  • Pyrin, a protein encoded by the MEFV gene, plays a vital role in innate immunity by sensing modifications in Rho GTPase and assembling the pyrin inflammasome, which in turn activates downstream immune responses. (bvsalud.org)
  • ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation. (kegg.jp)
  • PIG3 knockdown can suppress intra-S phase and G2/M checkpoints ( 8 ). (ijbs.com)
  • Downstream targets of CDKs include transcription factor E2F and its regulator Rb. (kegg.jp)
  • p53 and its transcriptional targets play an important role in both G1 and G2 checkpoints. (kegg.jp)
  • In order to completely understand the role of caspases in apoptosis, it is essential to identify their downstream targets. (cancercurehere.com)
  • HR comprises different pathways: gene conversion (GC) that accurately repair the lesion by copying the homologous sequence, single strand annealing (SSA) or break induced replication (BIR) that can both lead to loss of genetic information. (cea.fr)
  • These alterations can take the form of epigenetic modifications, point mutations, translocations, amplifications or deletions and modify gene functions in ways that deregulate cellular signalling pathways leading to the cancer phenotype. (bmj.com)
  • Furthermore, gene set enrichment analysis revealed upregulation of NLRC4-related pathways in patient PBMCs. (bvsalud.org)
  • The p53-inducible gene 3 (PIG3) recently has been reported to be a new player in DNA damage signaling and response, but the crucial mechanism remains unclear. (ijbs.com)
  • However, in certain cell types, the extrinsic pathway also induces mitochondrial damage by cleaving the pro-apoptotic Bcl-2 family protein Bid to its activated truncated form (tBid), which leads to Bak and Bax activation. (biologists.com)
  • 9 The exact number and nature of genetic alterations and deregulated signalling pathways required for tumorigenesis remains an issue of debate, 10 although it is now clear that central nervous system (CNS) carcinogenesis requires multiple disruptions to the normal cellular circuitry. (bmj.com)
  • These results provide a new insight into the mechanism of PIG3's functioning in DNA damage signaling and the regulation network of cellular DNA-PKcs expression homeostasis. (ijbs.com)
  • Small molecule inhibitors designed to target the DNA damage sensors, such as inhibitors of ataxia telangiectasia-mutated (ATM), ATR, CHK1 and WEE1, impair smooth cell cycle modulation and disrupt efficient DNA repair, or a combination of the above, have demonstrated interesting monotherapy and combinatorial activity, including the potential to reverse drug resistance and have entered developmental pipelines. (bmj.com)
  • SET8 depletion causes DNA damage specifically during replication, which induces a Chk1-mediated S-phase checkpoint. (rupress.org)
  • this protein prevents efficient repair of DNA damage, leading to the accumulation of mutations in other genes. (diff.org)
  • Future work in the lab will focus on identifying genes that induce DNA damage in response to short telomeres, identifying how telomeres are processed and how telomere elongation is regulated. (hopkinsmedicine.org)
  • We shall consider each subtype in turn describing genes and pathways of oncogenesis and how these relate to prognosis and treatment response. (springer.com)
  • Resection is accompanied by the binding of replication protein A (RPA) to the 3' single-stranded overhangs, which helps recruiting the checkpoint complexes. (cea.fr)
  • It encodes a large nuclear protein that is a component of DNA repair pathways. (lookformedical.com)
  • The BRCA2 protein is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (lookformedical.com)
  • It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (lookformedical.com)
  • However, a compensatory feedback of increased mRNA expression of DNA-PKcs was formed in PIG3-depleted cells after a few passages or cell cycles of subculture, which led the recovery of the DNA-PKcs protein level and the consequent recovered efficiency of the DNA damage response. (ijbs.com)
  • Maintaining genomic integrity is of utmost importance to eukaryotic cells, which have evolved sophisticated mechanisms to ensure speed, accuracy, and an adequate pool of nucleotide and replication factors as well as high-fidelity repair pathways to correct errors occurring during DNA replication. (bmj.com)
  • Persistent DNA damage can block transcription and replication and drives the aging process [ 25 ] . (encyclopedia.pub)
  • Exo1 has a role in several DNA repair pathways including MMR, post-replication repair, meiotic and mitotic recombination (14C16). (cancercurehere.com)
  • The concept has now been extended to embrace synthetic lethal drug sensitivity, such as that observed with PARP inhibitors in combination with DNA-damaging chemotherapy in a variety of BRCA defective tumors 10 . (nature.com)
  • Therefore, compared to normal p53-proficient cells, p53-defective cells are more reliant on MK2 activity, which drives an alternative cell cycle checkpoint pathway that stabilizes the CKI inhibitors p27 Kip1 and Gadd45α in order to maintain G 1 /S and G 2 /M arrest after certain types of DNA damage 16 , 18 . (nature.com)
  • Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated. (kegg.jp)
  • Inhibitors of the glycolytic pathway, such as dichloroacetic acid (DCA) and 2-deoxy-d-glucose (2DG) are now being used in clinical studies as potential anticancer agents. (sigmaaldrich.com)
  • Therefore, many genetically programmed cell suicide pathways have evolved to promote long-term survival of species from yeast to humans. (hopkinsmedicine.org)
  • GVHD is mediated by donor-derived T cells which recognize and damage genetically distinct normal host tissues. (umaryland.edu)
  • Akt2 is an important signaling molecule in the insulin signaling pathway. (aktinhibitor.com)
  • One of the treatments applied in cancer is radiotherapy (RT), a therapeutic modality that uses ionizing radiation to induce damage in unwanted cells. (frontiersin.org)
  • By contrast, the extrinsic apoptotic pathway can activate caspases without the participation of mitochondria. (biologists.com)
  • Because most tumors are deficient in one or more aspects of the function of the p53 tumor suppressor, either as a consequence of mutations within p53, or impairment of upstream and downstream modulators of p53 activity 19 , targeting MK2 has the potential to selectively enhance tumor cell killing without increasing the genotoxic effects of chemotherapy on normal p53-wild type tissues. (nature.com)
  • Unrepaired or incorrectly repaired DNA damage may lead to loss of heterozygosity, mutations, deletions, genomic rearrangements and chromosome loss. (cea.fr)
  • Apoptosis is essential for the removal of damaged cells, which would have the potential to carry deleterious mutations onto daughter cells. (cancercurehere.com)
  • Intrinsic factors include chronically activated proliferative, invasive, and antiapoptotic signaling pathways. (springer.com)
  • The PI3K pathway is considered to be a major determinant of the glycolytic phenotype through AKT1 and mTOR signaling, and subsequent downstream Hypoxy Inducible Factor 1 (HIF-1) transcription factor activation. (sigmaaldrich.com)
  • Additionally, PIG3 mediates cancer cell death through the GPx3 pathway, and knocking down PIG3 or blocking the interaction between PIG3 and GPx3 would abolish the increase in ROS and apoptosis ( 5 ). (ijbs.com)
  • The activity of NEK6 plays important roles in mitotic spindle kinetochore fiber formation, metaphase-anaphase transition, cytokinesis, and checkpoint regulation [ 3 , 4 ]. (hindawi.com)
  • Our findings suggest that inflammasome activation may be a critical driver in the pathogenicity of lupus, and autoinflammatory pathways may play important roles in the development of the disease. (bvsalud.org)
  • Having said that, no matter whether c Abl mediated regulation of MST1 and MST2 plays some distinct roles in other conditions is JNK Pathway always to be an exciting question in the future scientific studies. (aktinhibitor.com)
  • Specifically, we are studying cancer patients and mouse models to delineate the roles and mechanisms by which the beta2-adrenergic signaling pathway, the CD27/CD70 pathway, and the perforin/granzyme pathway impact the GVH and GVT responses. (umaryland.edu)
  • The interleukin 1 (IL-1) pathway signals through IL-1 receptor type 1 (IL-1R1) and emerges as a central mediator for systemic inflammation. (bvsalud.org)
  • To pursue a research career with a goal to improve cancer treatment, I enrolled in PhD training at the University of Florida in Dr. Stratford May's laboratory where I studied the biochemical pathways regulating cell death in the setting of blood cancers. (umaryland.edu)
  • These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment. (nature.com)
  • In the present study, the potential mechanism of PIG3 participation in the DNA damage response induced by ionizing radiation (IR) was investigated in multiple cell lines with depleted expression of PIG3 transiently or stably by the small interference RNA and lentivirus-mediated shRNA expression strategies. (ijbs.com)
  • The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. (lookformedical.com)
  • doi:10.1371 MEK inhibitor cancer journal.pone.0036562.g002 A Conserved Signaling Pathway in Neuron Apoptosis PLoS One particular www.plosone.org 4 May perhaps 2012 Volume 7 Difficulty 5 e36562 Elements and Techniques Plasmids and transfection The plasmids made use of have been as follows: pCMV Myc c Abl was a present from Dr. Cheng Cao. (aktinhibitor.com)
  • Abstract Ionizing radiation is frequently used to treat solid tumors, as it causes DNA damage and kill cancer cells. (techscience.com)
  • Cytotoxic drugs damage DNA and kill many normal cells as well as cancer cells. (msdmanuals.com)
  • Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. (springer.com)
  • The mechanisms of radioresistance are still poorly understood, despite it has been suggested that miRNAs play an important role in cell signaling pathways. (frontiersin.org)
  • Specifically, the concepts of tumour heterogeneity, oncogene addiction, non-oncogene addiction, tumour initiating cells, tumour microenvironment, non-coding sequences and DNA damage response will be reviewed. (bmj.com)
  • The main goal of RT consists in delivering a precise dose of radiation in a target volume, such as tumor, promoting the tumor cells eradication with as minimal damage as possible in surrounding normal tissues ( 13 ). (frontiersin.org)
  • These pathways lead to repair of the damaged DNA and their composition is dependant on the type of damage. (cancercurehere.com)
  • Strategies that increase replicative stress while lowering cell cycle checkpoint thresholds may allow unrepaired DNA damage to be inappropriately carried forward in replicating cells, leading to mitotic catastrophe and cell death. (bmj.com)
  • The DNA double-strand break (DSB) is considered to be the most severe type of DNA damage induced by ionizing radiation, and this form of DNA damage must be repaired immediately to prevent cell death. (ijbs.com)
  • Apoptosis and other forms of cell death are required for trimming excess, expired and damaged cells. (hopkinsmedicine.org)
  • J-H Lee et al extensively investigated the participation of PIG3 in DNA damage checkpoints after UV irradiation or after treatment using the radiomimetic drug neocarzinostatin (NCS) ( 8 ). (ijbs.com)