• 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)
  • Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors. (figshare.com)
  • Targeting the ATR, CHK1, and WEE1 kinases in Ewing sarcoma cells activates CDK2 and increases DNA replication stress by promoting the proteasome-mediated degradation of RRM2. (figshare.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)
  • In this article, we will introduce a potent dual checkpoint kinase Chk1 and WEE1 inhibitor as a chemical BMP sensitizer, PD407824 . (immune-system-research.com)
  • Since Chk1 didn't score because of toxicity (Fig. S2), we rescreened the poisonous subset of genes at a lesser siRNA concentration leading to yet another 98 pools rating that included Chk1, PALB2, Wee1 and FANCM (Fig. S2D and Dining tables S1 and S2). (insulin-receptor.info)
  • 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)
  • Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ataxia telangiectasia and rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. (figshare.com)
  • Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. (figshare.com)
  • Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome. (figshare.com)
  • 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)
  • Metformin generates a mild and transient inhibition of the mTOR pathway, suggesting that ongoing therapy would be needed for best effects. (naturalmedicinejournal.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)
  • Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). (unicatt.it)
  • TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. (unicatt.it)
  • Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. (nature.com)
  • When JNK signalling pathway is blocked by inhibitor SP600125, hepatic stellate cells (HSCs) activation is inhibited, with less proliferation and reduced expression of α-smooth muscle actin (α-SMA) [ 15 ]. (biomedcentral.com)
  • Analogous to the Chk1 kinase existing downstream of ATR, the Chk2 checkpoint kinase is modified and activated by ATM. (reactome.org)
  • In a recent study, Wilsker and colleagues from the Johns Hopkins University School of Medicine, Baltimore, used a panel of genetically modified human cancer cells to identify the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. (ascopost.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)
  • Previous data suggested that Cuc B triggered cell cycle arrest by blocking the STAT3 signaling pathway, which resulted in reduced expression of downstream targets, like Cyclin B1, Cyclin A [402]. (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)
  • Our research team previously showed that death receptors, which must be present on the cell surface in order for this pathway to be activated, are inhibited from going to the cell surface when the signaling molecule protein kinase Cβ is activated. (mayo.edu)
  • Chk1 is a checkpoint kinase activated during genotoxic stress. (reactome.org)
  • 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)
  • Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. (reactome.org)
  • Cs sPLA2 of C. sinensis may lead to liver fibrosis and HSCs activation which is related to c-Jun N-terminal kinase (JNK) signalling pathway. (biomedcentral.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)
  • The aim of this study was to determine the role of ataxia telangiectasia and RAD3-related (ATR)/checkpoint kinase 1 (Chk1) in AICAr-mediated differentiation of leukemia cells using metabolic tests, liquid chromatography with tandem mass spectrometry (LC/MS/MS), Western blot, flow cytometry, pharmacological inhibitors and RNA-interference. (nsk.hr)
  • Cross-talk between many of these pathways links cyclin B levels indirectly to induction of apoptosis. (wikipedia.org)
  • A decrease in survivin levels and the associated mitotic disarray triggers apoptosis via caspase 3 mediated pathway. (wikipedia.org)
  • One pathway leading to apoptosis, the so-called extrinsic or death receptor pathway, involves tumor cell killing that is initiated by cytotoxic T lymphocytes and natural killer cells. (mayo.edu)
  • The other major pathway leading to apoptosis is the intrinsic pathway, called the mitochondrial pathway. (mayo.edu)
  • Caspase-2 is most well-known for initiating the intrinsic apoptosis pathway [1] and as a tumor suppressor [2]. (nature.com)
  • While other groups have demonstrated non-apoptotic roles for caspase-2 in DNA repair, cell cycle arrest [2], this is the first demonstration that these roles are regulated by a distinct pathway to apoptosis. (nature.com)
  • The cyclin B/CDK1 complex also interacts with a variety of other key proteins and pathways which regulate cell growth and progression of mitosis. (wikipedia.org)
  • 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)
  • The proteins are part of a newly discovered DNA-protection pathway that potentially could be targeted to improve cancer therapies, according to researchers at Washington University School of Medicine in St. Louis. (wustl.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)
  • 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)
  • 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)
  • ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation. (kegg.jp)
  • Over the years, You and colleagues have identified eight protein factors involved in this genome-protection pathway. (wustl.edu)
  • ZEB1 achieves this unfortunate result through a complex chain of events that permit a gene known as ATM to stabilize the protein Chk1 that plays an important role in DNA damage response. (mdanderson.org)
  • Human DNA topoisomerase II-binding protein 1 (hTopBP1) plays an important role in DNA replication and the DNA damage checkpoint pathway. (biomedcentral.com)
  • The ataxia telangiectasia and Rad3-related protein (ATR) signaling cascade is an important pathway involved in the checkpoint control mechanism [ 3 ]. (biomedcentral.com)
  • A study in 2009 found that cyclin B overexpression in ovarian cancer indicates that the cancer is unlikely to be malignant while more aggressive ovarian cancers of epithelial cell origin do not show elevated cyclin B. There is strong cross-talk between the pathways regulating cyclin B and the tumor suppressor gene p53. (wikipedia.org)
  • 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)
  • Lossaint G*, Horvat A *, Gire V, Bačević K, Mrouj K, Charrier-Savournin F, Georget V, Fisher D, Dulić V (2022) Reciprocal regulation of p21 and Chk1 controls the cyclin D1-RB pathway to mediate senescence onset after G2 arrest. (irb.hr)
  • While the ATR and ATM pathways are distinct, there is interplay between the two. (reactome.org)
  • We propose a model where caspase-2 regulates the cell cycle and protects DNA replication forks to prevent DNA damage accrual in a pathway distinct from its apoptotic role. (nature.com)
  • Thus, caspase-2 activation during replication stress engages a pathway distinct from that engaged by cytokinesis failure. (nature.com)
  • Notably, a number of different cancers, including Ewing sarcoma tumors, are sensitive to the combination of RNR and ATR-CHK1 inhibitors. (figshare.com)
  • However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single agents and in combination with RNR inhibitors, toward cancer cells. (figshare.com)
  • In this regard, they noted that dactinomycin and bortezomib (Velcade), for example, induced a similar dependence on ATR pathways for cell growth after treatment, despite having highly dissimilar mechanisms of action-a finding suggesting that "there may be many avenues by which ATR inhibitors might provide enhanced therapeutic effects. (ascopost.com)
  • By combining inhibitors of this pathway with chemotherapy drugs that target the DNA replication process, we potentially could make such drugs more effective. (wustl.edu)
  • Inducing cell cycle arrest by cucurbitacins has been B7-2/CD86 Inhibitors targets properly Methyl-PEG3-Ald custom synthesis established while the detailed mechanisms and pathways are largely to become clear. (achrinhibitor.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)
  • SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence. (cdc.gov)
  • Combined with the other studies in the Anticancer Drug Action Lab, our studies of apoptotic pathways are providing new insight into factors that govern cancer cell sensitivity to targeted anti-cancer agents and immunotherapy, while also elucidating the mechanisms of resistance to a variety of novel anti-cancer agents. (mayo.edu)
  • These observations, which are currently being explored in greater detail, lay the foundation for efforts to increase the efficacy of immunotherapy by modulating the death receptor pathway in various tumors. (mayo.edu)
  • The Response To Uv Pathway has been researched in relation to Dna Repair, Cell Cycle, Cell Death, Dna Replication, Cellular Response To Uv. (novusbio.com)
  • The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. (oncotarget.com)
  • ToxTracker is a mammalian stem cell-based assay that monitors activation of specific cellular signalling pathways for detection of the biological reactivity of compounds. (europa.eu)
  • Stem cells are genetically stable and proficient in all cellular pathways required for accurate detection of potentially carcinogenic properties of compounds. (europa.eu)
  • 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)
  • Notably, we found that the expression of the CHK1 phosphatase PP1α is increased in Spi1/PU.1-overexpressing cells. (oncotarget.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)
  • Stresses that activate ATM, e.g., ionizing irradiation, do not cause significant Chk1 activation. (reactome.org)
  • 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)
  • The JNK signalling pathway is involved in hepatic stellate cells (HSCs) activation. (biomedcentral.com)
  • Western blot of mouse liver was done to detect the activation of JNK signalling pathway. (biomedcentral.com)
  • In vitro, HSCs were incubated with MBP- Cs sPLA2 to detect the activation of HSCs as well as the activation of JNK signalling pathway. (biomedcentral.com)
  • In vitro , MBP- Cs sPLA2, as well as the mutant, was incubated with HSCs and it was proved that activation of HSCs was related to activation of the JNK signalling pathway instead of the enzymatic activity of MBP- Cs sPLA2. (biomedcentral.com)
  • Activation of HSCs by Cs sPLA2 is related to the activation of the JNK signalling pathway instead of the enzymatic activity of Cs sPLA2. (biomedcentral.com)
  • 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)
  • Thus, hTopBP1 constitutes an important part of the ATR signaling pathway and acts as a molecular bridge that associates the independently recruited 9-1-1 and ATR-ATRIP complexes, thereby leading to checkpoint activation [ 4 ]. (biomedcentral.com)
  • All of these defects are associated with impaired activation of the ATR/CHK1 pathway. (nature.com)
  • However, in the absence of caspase-2, we observed some impairment of ATR autophosphorylation, but we did not detect any differences in CHK1 activation. (nature.com)
  • harm from the 9-1-1 is and organic essential to promote Chk1 activation. (insulin-receptor.info)
  • Li Ma, Ph.D., an assistant professor of experimental radiation oncology at MD Anderson, reported in this month's issue of Nature Cell Biology that ZEB1 may actually be helping breast tumor cells repair DNA damage caused by radiation treatment by ramping up a first-line of defense known as DNA damage response pathway. (mdanderson.org)
  • The hope is that new approaches to addressing radiation resistance may be developed through gaining better insight into how this signaling pathway keeps tumor cells growing despite being bombarded with toxic radiation treatments. (mdanderson.org)
  • To overcome the obstacle of radioresistant tumor cells, it is important to identify the critical causes and to develop safe and effective new methods for treatment including the possible use of agents that target ZEB1 and which inhibit CHK1. (mdanderson.org)
  • Targeted gene disruption in mice shows that loss of Chk1 causes peri-implantation embryonic lethality. (reactome.org)
  • Therefore, a metabolic shift from mitochondrial respiration to the glycolytic pathway occurs during OB differentiation. (nih.gov)
  • 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)
  • 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)
  • The need for the DNA harm response (DDR) can be underscored from the prevalence of mutations with this pathway within malignancies and developmental syndromes (1). (insulin-receptor.info)
  • Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage. (nih.gov)
  • Avoiding damage formation through invalidation of Mus81-Eme2 and Mre11, or preventing damage signaling by turning off the ATM pathway, suppresses the replication phenotypes of Chk1-deficient cells. (nih.gov)
  • Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. (kegg.jp)
  • These results identify a novel pathway by which an oncogene influences replication in the absence of DNA damage. (oncotarget.com)
  • Researchers at Washington University School of Medicine in St. Louis have identified a previously unknown signaling pathway cells use to protect their DNA while it is being copied. (wustl.edu)
  • In conclusion, PD407824 sensitizes cells to BMP4-induced upregulation of BMP pathway target genes, including Id1 and Id2. (immune-system-research.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)
  • 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)
  • Laverne is a handy bioinformatics tool to help facilitate scientific exploration of related genes, diseases and pathways based on co-citations. (novusbio.com)
  • Like ATR, Chk1 is essential for viability in mammals. (reactome.org)
  • The findings, published Jan. 24 in the journal Molecular Cell, suggest that targeting this pathway potentially could boost the potency of cancer therapeutics. (wustl.edu)
  • The ATR/Chk1 pathway is a crucial surveillance network that maintains genomic integrity during DNA replication by stabilizing the replication forks during normal replication in order to avoid replication stress. (molecularcircuit.com)
  • Early in his career, he worked on the ATR-Chk1 genome-protection pathway - a pathway that controls the cell-division cycle and prevents stalled replication machinery from failing entirely and causing breaks in the DNA. (wustl.edu)
  • A p53 dependent checkpoint pathway prevents re-replication. (nii.res.in)