• The accumulation of hTopBP1 on chromatin and its subsequent interaction with hRad9 lead to cell cycle arrest, a process mediated by Chk1 phosphorylation and ataxia telangiectasia and Rad3-related protein (ATR) activation. (biomedcentral.com)
  • Chk1 is regulated by ATR through phosphorylation, forming the ATR-Chk1 pathway. (wikipedia.org)
  • Additional protein interactions are involved to induce maximal phosphorylation of Chk1. (wikipedia.org)
  • Firstly, DNA damage stabilizes SCML2 through CHK1-mediated phosphorylation at Ser570. (lucmg.com)
  • Although viewed as a constitutive housekeeping enzyme in the past, PP2A is a highly regulated phosphatase and is emerging as an important regulator of multiple cellular processes involving protein phosphorylation. (ac.be)
  • But advances in the understanding of protein phosphatases make now clear that these enzymes are precisely regulated and are as important as kinases in the regulation of cellular processes involving protein phosphorylation. (ac.be)
  • Activation of Chk1 occurs following phosphorylation of two sites (serine 317 and serine 345). (reactome.org)
  • Mutational analysis indicates that modification of both sites is essential for maximal kinase activity, while phosphorylation of only a single site causes only weak activation of Chk1. (reactome.org)
  • Following phosphorylation, Chk1 can diffuse away from the complex to further amplify the checkpoint signal. (reactome.org)
  • Here, we demonstrate that the S phase checkpoint protein CHK1 is maintained in a low phosphorylation state in Spi1/PU.1-overexpressing cells and provide evidence that this is not due to negative control of its primary kinase ATR. (oncotarget.com)
  • Cuc B induced phosphorylation of Chk1 on Ser-345, phosphorylation of Cdc25C on Ser-216, and phosphorylation p53 on Ser-15 had been all inhibited by ATM knockdown (Fig. 4C). (achrinhibitor.com)
  • Additionally, Cuc B brought on phosphorylation of your Chk1 downstream effector Cdc25C on Ser-216 and Cdk1 on Tyr15 had been also inhibited (Fig. 5C).Cuc B induced ROS generation and didn't influence STAT3 phosphorylationRecent research have shown that Cuc B induced intracellular ROS formation in HeLa, SW480, and B16F10 cells [14,15,39]. (achrinhibitor.com)
  • TLK1 in particular is inactivated rapidly in response to double-stranded breaks via ATM and Chk1-dependent phosphorylation at S695 and thus represents a regulatory THZ1 link between cell cycle progression and checkpoint function [41 42 Direct Chk1-induced inhibition of TLK1 can be transient and TLK1 activity comes back to baseline amounts later on in the harm response. (biotech-angels.com)
  • In addition, we investigated several cell cycle-related proteins and found that co-knockdown of hTopBP1 and hMYH significantly diminished cell cycle arrest due to compromised checkpoint kinase 1 (Chk1) activation. (biomedcentral.com)
  • Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. (wikipedia.org)
  • Two checkpoint kinase subtypes have been identified, Chk1 and Chk2. (wikipedia.org)
  • Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. (nature.com)
  • In contrast, downstream signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses for a smaller subset of the drugs tested. (ascopost.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 a central component of genome surveillance pathways and is a key regulator of the cell cycle and cell survival. (wikipedia.org)
  • Differentially regulated pathways were characteristic of high-grade meningiomas. (nature.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)
  • Building on these earlier results, current studies in our lab focus on understanding the pathways that lead to caspase activation and the mechanisms that regulate those pathways. (mayo.edu)
  • These included PI3K/AKT pathway proteins, those regulating the cell cycle, apoptosis, transcription, and other signaling pathways including steroid hormone signaling. (biomedcentral.com)
  • Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). (unicatt.it)
  • Our work focuses on the understanding the molecular pathways that regulate and coordinate the cell cycle, transcription, and chromatin regulation. (dartmouth.edu)
  • These findings indicate that specific inhibition of the Cdk2/ATR/Chk1 pathway with distinct regulating agents could differentially sensitize cancer cells to a wide range of therapeutic agents. (ascopost.com)
  • In addition, our recent studies have implicated the death receptor pathway in the TP53-independent anti-leukemic effects of inhibitors of the kinases Chk1, ATR and Wee1 as single agents. (mayo.edu)
  • This pathway is regulated by a family of proteins called BCL2 family members that monitor the intracellular environment and regulate the integrity of mitochondria. (mayo.edu)
  • This was regulated by the hedgehog pathway (Gli2, Bmi1, and Sox 2) to promote tumour initiation and maintenance [41]. (globaltechbiz.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)
  • The ATM activated Chk1-Cdc25C-Cdk1 pathway was additional investigated. (achrinhibitor.com)
  • Human genome codes for many other single strand DNA binding proteins and we are testing if novel mechanisms of checkpoint activation exist that do not require Replication Protein A. If such mechanisms exist we would like to understand which factors provide the role of DNA binding, how checkpoint proteins like Chk1 and p53 are activated and how signal transduction pathway stalls the cell cycle and DNA replication. (nii.res.in)
  • Co-inhibition of IGF and CHK1 caused synergistic suppression of cell viability, cell survival and tumour growth in 2D cell culture, 3D spheroid cultures and in vivo. (nature.com)
  • Investigating the mechanism of synthetic lethality, we reveal that CHK1 inhibition in IGF-1R depleted or inhibited cells further downregulated RRM2, reduced dNTP supply and profoundly delayed replication fork progression. (nature.com)
  • Chk1 facilitates the arrest of cell cycle progression and the inhibition of replication origin firing. (caltech.edu)
  • Indeed, PARP and CHK1 inhibition by AZD2461 and UCN-01, by downregulating c-Myc, reduced the expression of XBP1s, constitutively expressed in these cells, and upregulated CHOP. (uniroma1.it)
  • Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle. (wikipedia.org)
  • Chk1 is required for the initiation of DNA damage checkpoints and has recently been shown to play a role in the normal (unperturbed) cell cycle. (wikipedia.org)
  • In addition to mediating cell cycle checkpoints, Chk1 also contributes to DNA repair processes, gene transcription, egg production, embryo development, cellular responses to HIV infection and somatic cell viability. (wikipedia.org)
  • Chk1 has a regulatory role in the spindle checkpoint however the relationship is less clear as compared to checkpoints in other cell cycle stages. (wikipedia.org)
  • DNA damage induces the activation of Chk1 which facilitates the initiation of the DNA damage response (DDR) and cell cycle checkpoints. (wikipedia.org)
  • During the cell cycle, there are two main checkpoints that regulate entrance into S and M phases. (vt.edu)
  • In order to understand the function and regulation of Chk1 in checkpoints, the features of the MBT that activate Chk1 must be identified. (vt.edu)
  • The transition of one phase to the other in the Go/G1, S, and G2/M phases of the cell cycle in malignancy cells occurs only after passing through the checkpoints, regulated by cyclins and CDKs, which is usually impaired in malignancy. (globaltechbiz.com)
  • hTopBP1 and hMYH were involved in ATR-mediated Chk1 activation, moreover, both of them were associated with ATR and hRad9 which known as checkpoint-involved proteins. (biomedcentral.com)
  • Chk1 must inactivate in order for the cell to transition from the G2 phase into mitosis, Chk1 expression levels are mediated by regulatory proteins. (wikipedia.org)
  • However, activation of Chk1 is not solely dependent on ATR, intermediate proteins involved in DNA replication are often necessary. (wikipedia.org)
  • Regulatory proteins such as replication protein A, Claspin, Tim/Tipin, Rad 17, TopBP1 may be involved to facilitate Chk1 activation. (wikipedia.org)
  • However, chromatin binding-deficient Claspin proteins can still mediate Chk1 activation in Claspin-depleted extracts, albeit with reduced efficiency. (caltech.edu)
  • Claspin mutant proteins unable to interact with DDK still bind to Chk1 and rescue Chk1 activation in Claspin-depleted extracts. (caltech.edu)
  • Whenever genomic lesions are detected during DNA synthesis, they are coated by the single strand DNA binding protein complex, called Replication Protein A, leading to the activation of canonical checkpoint proteins like ATR, Chk1 and p53. (nii.res.in)
  • In response to DNA harm phosphatidylinositol (PI)-3 kinase-related kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) are primarily activated and eventually phosphorylate several proteins including Rad17 as well as the Chk1 kinase. (biobender.com)
  • The ATR-Chk1 axis is certainly central towards the DDR and crucial for preserving genome integrity and they're regarded as DNA harm sensor proteins in cells. (biobender.com)
  • By exogenously modulating its activity, we demonstrate that PP1α is required to maintain CHK1 in a dephosphorylated state and, more importantly, that it is responsible for the accelerated replication fork progression in Spi1/PU.1-overexpressing cells. (oncotarget.com)
  • CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. (kegg.jp)
  • Emerging evidences suggest that microRNA target genes that regulate DNA replication and cell cycle progression and we aim to determine how microRNA regulate the DNA replication machinery as cell progresses from one phase to the next. (nii.res.in)
  • To develop effective targeted therapies for OS, extensive studies on the molecular mechanisms regulating the progression of OS are quite necessary. (biomedcentral.com)
  • Although having distinct structures, Chk1 and Chk2 also have overlapping targets with some substrate sites phosphorylatable by both kinases (e.g., serine 20 of p53). (reactome.org)
  • The focus of this study is the role of protein kinase Chk1 and the phosphatase Cdc25A in the DNA replication checkpoint. (vt.edu)
  • Notably, we found that the expression of the CHK1 phosphatase PP1α is increased in Spi1/PU.1-overexpressing cells. (oncotarget.com)
  • ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation. (kegg.jp)
  • Replication blockages activate the ATR kinase which, in turn, activates the downstream effector kinase Chk1 through the mediator protein, Claspin. (caltech.edu)
  • Similarly, Cuc mediated ATM downstream effector of p53, 14-3-3-s expression is down-regulated by ATM siRNA. (achrinhibitor.com)
  • Activation of STAT3 signaling could up-regulate Cyclin B1, c-Myc, Bcl-x and regulating cell growth and survival.Chk1 knockdown reversed Cuc B induced G2/M phase arrestTo dissect the downstream effector in Cuc B mediated G2/M phase arrest, the part of Chk1 was examined with Chk1 siRNA. (achrinhibitor.com)
  • SET8 depletion causes DNA damage specifically during replication, which induces a Chk1-mediated S-phase checkpoint. (rupress.org)
  • In the absence of active Chk1, Cdc25A activates cyclin dependent kinases (Cdks) allowing the cell to progress into S or M phase. (vt.edu)
  • Chk1 regulates cell cycle arrest in the presence of unreplicated DNA in somatic cells by phosphorylating Cdc25A and leading to its degradation. (vt.edu)
  • Embryos treated with aphidicolin, resulting in a halted replication fork and therefore a reduced DNA concentration, were tested for Chk1 activation and Cdc25A degradation. (vt.edu)
  • Chk1 and Cdc25A were observed to undergo activation and degradation, respectively, in embryos with a reduced DNA concentration. (vt.edu)
  • In addition, embryos were injected with Δ34Xic cyclin E/Cdk2 inhibitor, in order to disturb the maternal timer and tested for Chk1 activation and Cdc25A degradation. (vt.edu)
  • Both Chk1 and Cdc25A were unaffected by the disruption of the cyclin E/Cdk2 maternal time in the embryo. (vt.edu)
  • Therefore, the N/C ratio and the cyclin E/Cdk2 maternal timer do not affect Chk1 activation and therefore Cdc25A degradation. (vt.edu)
  • 2021. Excess histone H3 is a competitive Chk1 inhibitor that controls cell-cycle remodeling in the early Drosophila embryo . (dartmouth.edu)
  • Chk1 activation can also be ATR-independent through interactions with other protein kinases such as PKB/AKT, MAPKAPK and p90/RSK. (wikipedia.org)
  • Many cancers show aberrant signalling via the insulin-like growth factor (IGF) axis, activating type 1 IGF receptors (IGF-1Rs) and variant insulin receptors (INSRs) to signal via phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) and mitogen-activated protein kinase kinase-extracellular signal-regulated kinases (MEK-ERK) [ 1 ]. (nature.com)
  • The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. (unicatt.it)
  • TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. (unicatt.it)
  • Like ATR, Chk1 is essential for viability in mammals. (reactome.org)
  • Recently, Chk1 has shown to mediate DNA repair mechanisms and does so by activating various repair factors. (wikipedia.org)
  • Claspin has two broadly defined roles, one to mediate Chk1 activation and the other as a component of the replication fork. (caltech.edu)
  • In COAD cells, NEK6 was highly expressed, whereas miR-323a-3p was expressed at low levels and negatively regulated NEK6. (hindawi.com)
  • Considering that the 9-1-1 complicated is necessary for damage-induced Chk1 activation [17 29 we had been intrigued by the idea a substrate of Chk1 may regulate Rad9 and therefore fine-tune the checkpoint response. (biotech-angels.com)
  • Knockdown of BAF250a by siRNA in three CCC cell lines wild type for ARID1A showed no increase in either pAKT-Thr 308 or pAKT-S 473 suggesting that pAKT in tumor tissues is indirectly regulated by BAF250a expression. (biomedcentral.com)
  • Exogenous RRM2 expression rescued hallmarks of replication stress induced by co-inhibiting IGF with CHK1 or WEE1, identifying RRM2 as a critical target of the functional IGF:CHK1 and IGF:WEE1 interactions. (nature.com)
  • Constitutive expression of Chk1 in fission yeast was shown to induce cell cycle arrest. (wikipedia.org)
  • Studies on Chk1 deficient chicken lymphoma cells have shown increased levels of genomic instability and failure to arrest during the spindle checkpoint phase in mitosis. (wikipedia.org)
  • Within this study, we showed that Cuc B induced G2/M arrest inside a ROS dependent manner without having affecting STAT3 in A549 cells: Cuc B induced ROSmediated DNA harm, which activated G2/M phase checkpoint through ATM-activated Chk1-Cdc25C-Cdk1 and -p53-14-3-3-s cascades. (achrinhibitor.com)
  • Comparable to that of ATM siRNA, Cuc B- induced G2/M arrest in A549 cells was substantially decreased by Chk1 siRNA therapy (Fig. 5A, 5B). (achrinhibitor.com)
  • This proceeds to phosphorylating a number of protein that regulate the DNA-damage response (DDR) including cell routine arrest stabilization of stalled replication forks and DNA fix [32]. (biobender.com)
  • Furthermore, Chk1 has been associated with three particular aspects of the S-phase, which includes the regulation of late origin firing, controlling the elongation process and maintenance of DNA replication fork stability. (wikipedia.org)
  • In p53-mutant or p53-negative cancer cells, SCML2 promotes CHK1 and p21 stability by inhibiting their ubiquitination, thereby enhancing the resistance to DNA damage agents. (lucmg.com)
  • Interestingly, we found that SCML2A primarily stabilizes CHK1, while SCML2B regulates the stability of p21. (lucmg.com)
  • Several signaling mechanisms that regulate development and pattern formation in vertebrates, including humans, have been found in hydra. (ehu.eus)
  • In 1993, Beach and associates initially identified Chk1 as a serine/threonine kinase which regulates the G2/M phase transition in fission yeast. (wikipedia.org)
  • Chk1 is essential for the maintenance of genomic integrity. (wikipedia.org)
  • These findings indicate that miR-323a-3p regulates the proliferation, migration, invasion, and apoptosis of COAD cells by targeting NEK6. (hindawi.com)
  • A number of lncRNAs have been shown to regulate cellular processes including proliferation, apoptosis and differentiation in diverse physiological and pathological contexts [ 1 ]. (biomedcentral.com)
  • The activation of Chk1 by two time-dependent events in the cell cycle, the critical nuclear to cytoplasmic (N/C) ratio and the cyclin E/Cdk2 maternal timer are explored in this study. (vt.edu)
  • Additionally, Cuc B up-regulated Cyclin B1 was also reversed by ATM siRNA (Fig. 4C). (achrinhibitor.com)
  • Even though ATR-ATRIP not bound to ssDNA can phosphorylate Chk1, Chk1 activation is greatly enhanced when recruited to stalled replication forks by physical interaction with a modified form of claspin and the Rad9-Hus1-Rad1 sliding clamp. (reactome.org)
  • Nuclear pMST1/2 (pMST1/2nuc) expression was significantly associated with nuclear expression of Chk1 (p = 0.046), whereas cytoplasmic pMST1/2 (pMST1/2cyt) expression was marginally associated with cytoplasmic TAZ staining (p = 0.053). (unicatt.it)
  • In mitosis, ATR localizes to centromeres through Aurora A-regulated association with centromere protein F (CENP-F), allowing ATR to engage replication protein A (RPA)-coated centromeric R loops. (umn.edu)
  • During this phase the Chk1 activating element of ssDNA can not be generated suggesting an alternate form of activation. (wikipedia.org)
  • Targeted gene disruption in mice shows that loss of Chk1 causes peri-implantation embryonic lethality. (reactome.org)
  • Stresses that activate ATM, e.g., ionizing irradiation, do not cause significant Chk1 activation. (reactome.org)
  • WRN critically regulates autophagy in various cellular stresses, including starvation, endoplasmic reticulum (ER) stress conditions to rescue the cell, and basal situations to restore proper cellular function. (nih.gov)
  • 2019. Histone concentration regulates the cell cycle and transcription at the mid-blastula transition . (dartmouth.edu)
  • Our results suggested that hMYH is necessary for the accumulation of hTopBP1 to DNA damage lesion to induce the association of hTopBP1 with 9-1-1 and that the interaction between hMYH and hTopBP1 is essential for Chk1 activation. (biomedcentral.com)
  • In response to DNA damage, Chk1 is an important signal transducer for G2/M checkpoint activation. (wikipedia.org)
  • Activation of Chk1 holds the cell in the G2 phase until ready to enter the mitotic phase. (wikipedia.org)
  • Thus, the localization of Claspin to the replication fork is not required for mediation of Chk1 activation but it does potentiate this process. (caltech.edu)
  • For example, double-strand DNA breaks can be processed in an ATM-dependent manner to generate structures that can cause ATR and hence Chk1 activation. (reactome.org)
  • As ATR is activated at centromeres, it stimulates Aurora B through Chk1, preventing formation of lagging chromosomes. (umn.edu)
  • First, given evidence that IGFs regulate the response to IR, we also found evidence that IGF-1R depletion induced endogenous DNA lesions marked by γH2AX foci in prostate cancer cells [ 10 ]. (nature.com)
  • Accumulation of Drf1 on chromatin in the presence of replication blocks is dependent upon ATR and Claspin but not Chk1. (caltech.edu)
  • Moreover, we identified a region of Claspin required for association with DDK that lies within the Chk1-binding domain, which contains a series of repeat sequences. (caltech.edu)
  • Chk1 plays a critical but not fully understood role in cell cycle remodeling and early embryonic development. (vt.edu)
  • Interestingly, given the role of XBP1s in regulating DDR, BRCA-1 expression level was reduced, exacerbating DNA damage. (uniroma1.it)
  • ATR appears to be the primary kinase activating Chk1 as conditions that activate ATR (ultraviolet irradiation or treatment with hydroxyurea) also activate Chk1. (reactome.org)
  • We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. (elsevierpure.com)
  • These results provide evidence that the involvement of mitophagy is crucial during OB differentiation, and KLF2 critically regulates it. (nih.gov)
  • It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. (biomedcentral.com)
  • Through these findings, it is apparent Chk1 is highly conserved from yeast to humans. (wikipedia.org)