• 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. (utsouthwestern.edu)
  • This kinase has been shown to phosphorylate checkpoint kinase CHK1, checkpoint proteins RAD17, and RAD9, as well as tumor suppressor protein BRCA1. (utsouthwestern.edu)
  • B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. (rafinhibitors.com)
  • Compared to HL60 cells, the tyrosine phosphorylation level in K562 cells was markedly increased, suggesting that the increase in tyrosine phosphorylation is due to BCR ABL tyrosine kinase activity, which was confirmed by the expression of BCR ABL shown only in K562 cells. (rafinhibitors.com)
  • Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. (abcam.cn)
  • The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast. (academicinfluence.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 S. cerevisiae checkpoint protein Rad17, the orthologue of human Rad1, forms a homocomplex in response to treatment with DNA damaging agents, and the complex is required for yeast survival after exposure to genotoxic agents [ 12 ]. (biomedcentral.com)
  • TOPBP1 was first identified as a DNA damage protein through its association with BRCA1, which is a protein heavily implicated in breast cancer pathology. (wikipedia.org)
  • TOPBP1 was found in complex with BRCA1 at sites independent from replication forks (i.e identified by the DNA replication clamp proliferating cell nuclear antigen) during normal S phase. (wikipedia.org)
  • BRCA1 is a protein that has many variants of uncertain significance which are not yet classified as functionally normal or abnormal. (bvsalud.org)
  • Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. (bvsalud.org)
  • However, acquired resistance to PARPis has been reported for most tumors, and not all patients with BRCA1/2 mutations respond to PARPis. (bvsalud.org)
  • 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)
  • 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)
  • The anti-apoptotic Bcl-2 relative Bcl-xL as well as the antagonist BH3 just proteins Bak/Bax had been proven to regulate mitochondrial form in healthful cells aswell such as cells going through apoptosis [13] [14]. (tech-strategy.org)
  • We have also demonstrated previously overexpression of Rad9 mRNA in a number of primary breast tumors and the increased Rad9 mRNA was correlated with an increased risk of local recurrence and tumor proliferation, suggesting that Rad9 is an oncogene in breast cancer [ 8 ]. (biomedcentral.com)
  • The effects of heterozygous deletion of Mrad1 on proliferation and apoptosis of keratinocytes is different from those resulted from Mrad9 heterozygous deletion (from our previous study), suggesting that Mrad1 also functions independent of Mrad9 besides its role in the Mrad9-Mrad1-Mhus1 complex in mouse cells. (biomedcentral.com)
  • It is likely that increased Rad9 expression is needed for proliferation of tumor cells by mechanisms such as getting beyond (tolerating) oncogene-induced replicative stress and enhancing DNA repair capability. (biomedcentral.com)
  • These include DNA damage repair, DNA replication, transcriptional regulation, and cell cycle checkpoint activation. (wikipedia.org)
  • It also plays a critical role in DNA replication initiation and regulation of the cell cycle. (wikipedia.org)
  • This ssDNA will become coated with replication protein A (RPA). (wikipedia.org)
  • Normally, structural damage of DNA by endogenous and environmental agents is followed by replication checkpoint arrest at the G2/M transition in order to allow for repair before proceeding in the cell cycle. (biomedcentral.com)
  • The loss of proper response to DNA damage leads to genomic instability such as gene mutations, incomplete replication and the loss or gain of chromosomes to future generations. (biomedcentral.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)
  • Each origin is initiated by a combination of regulatory proteins that prepare the chromatin for replication before synthesis (S)-phase entry. (bmj.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)
  • Any obstacles encountered by cells in this process can lead to 'replicative stress' ( Figure 1 ), 1 which may be overcome by replicative stress response proteins, but deficiencies in this response result in accumulated errors in DNA replication and loss of genomic integrity, which lead to cell death. (bmj.com)
  • Human DNA topoisomerase II-binding protein 1 (hTopBP1) plays an important role in DNA replication and the DNA damage checkpoint pathway. (biomedcentral.com)
  • Human DNA topoisomerase II-binding protein 1 (TopBP1) and its orthologs play important roles in DNA replication and checkpoint control [ 1 ]. (biomedcentral.com)
  • It was also recently shown that PARP-1 is a sensor of unligated Okazaki fragments during DNA replication 16 and cells deficient in ribonucleotide excision repair are sensitized to PARP inhibition 17 . (nature.com)
  • Mutations of this gene are associated with Seckel syndrome. (utsouthwestern.edu)
  • Loss of function of oncogenes, tumor suppressor genes and DNA damage processing genes has been implicated in the development of many types of cancer, but for the vast majority of cases, there is no link to specific germ line mutations. (aacrjournals.org)
  • Interestingly, Wnt Pathway we found a significant increase in tyrosine phosphorylation at the corresponding molecular weight of hTERT in K562 cells compared to HL60 cells. (rafinhibitors.com)
  • To evaluate this possibility, hTERT was immunoprecipitated by anti hTERT antibody from both K562 and HL60 cell lysates and resolved by SDS PAGE followed by immunoblotting with anti phosphorylation antibody. (rafinhibitors.com)
  • We found that hTERT tyrosine phosphorylation was significantly elevated in K562 cells compared to HL60 cells. (rafinhibitors.com)
  • To further determine whether BCR ABL phosphorylates Raf Inhibitors hTERT, we treated K562 cells with 1 M Gleevec, and evaluated the phosphorylation status of hTERT. (rafinhibitors.com)
  • As shown in Figure 4c, Gleevec treatment resulted in almost complete inhibition of hTERT phosphorylation at tyrosine residues compared to control cells. (rafinhibitors.com)
  • To demonstrate that the decrease in tyrosine phosphorylation of hTERT was not due to reduced hTERT expression level, western blot was performed and we did not observe a difference in hTERT expression level in Gleevec treated K562 cells compared to control cells. (rafinhibitors.com)
  • Gleevec inhibits hTERT nucleoli translocation in K562 BCR ABL positive cells It is known that phosphorylation of hTERT is important for its nuclear translocation. (rafinhibitors.com)
  • Finally we shown that CTMP delayed PKB/Akt phosphorylation following cell death induction suggesting that CTMP regulates apoptosis via inhibition of PKB/Akt. (tech-strategy.org)
  • Mice heterozygous for a knock-out allele exhibit premature death and increased tumor incidence. (utsouthwestern.edu)
  • A major conclusion from these data is that, contrary to one of the current views on tumorigenesis, inactivation of one allele of a tumor suppressor gene is enough to contribute to tumor progression. (aacrjournals.org)
  • Delineating functionally normal variants from functionally abnormal variants in tumor suppressor proteins is critical for cancer surveillance, prognosis, and treatment options. (bvsalud.org)
  • TOPBP1 was first identified as a protein binding partner of DNA topoisomerase-IIβ by a yeast 2-hybrid screen, giving it its name. (wikipedia.org)
  • The Rad1 protein, evolutionarily conserved from yeast to humans, exists in cells as monomer as well as a component in the 9-1-1 protein complex. (biomedcentral.com)
  • Research with yeast resulted in the identification from the conserved mammalian "mitochondria-shaping" protein. (tech-strategy.org)
  • To further examine the role of hRad9 in breast cancer cells, we now report on the histologic expression of the hRad9 protein and its different molecular forms in primary breast cancer and normal tissues. (biomedcentral.com)
  • Elevated levels of replicative stress in gynecological cancers arising from uncontrolled oncogenic activation, loss of key tumor suppressors, and frequent defects in the DNA repair machinery are an intrinsic vulnerability for therapeutic exploitation. (bmj.com)
  • To address this issue, primary mouse cells, haploinsufficient for one or two proteins, ATM and RAD9, related to the cellular response to DNA damage were examined. (aacrjournals.org)
  • Confocal microscopy was carried out to study Gleevec,s effect on hTERT cellular distribution in K562, HL60, and Jurkat cells. (rafinhibitors.com)
  • Importantly, this enhanced cellular metabolic activity upon acute hyper activation of Bcr Abl was not beneficial for the cells as proposed by Warburg. (rafinhibitors.com)
  • Cells are constantly exposed to stresses from cellular metabolites as well as environmental genotoxins. (biomedcentral.com)
  • The cellular response to DNA damage involves an intricate network of enzymes responsible for sensing, signaling, and repairing damaged DNA, as well as the regulation of cell cycle checkpoints that collectively maintain genomic integrity 2 . (nature.com)
  • As an initial approach to examine the cellular program induced by TNF in Tregs versus Tcon cells, we employed microarray gene expression analysis at 2 and 24 hrs following TNF treatment. (gsea-msigdb.org)
  • DMBA-TPA combinational treatment was used to induce tumors on mouse skin. (biomedcentral.com)
  • We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. (bvsalud.org)
  • The TOPBP1 gene encodes a scaffold protein which facilitates interactions between different proteins at specific times and locations. (wikipedia.org)
  • These data suggest that Mrad1 is important for preventing tumor development, probably through maintaining genomic integrity. (biomedcentral.com)
  • hRad9 is a nuclear protein that interacts with hRad1 and hHus1 to form a hetero-trimeric complex (the 9-1-1 complex) which is then loaded onto DNA [ 9 ]. (biomedcentral.com)
  • Moreover, we observed that hMYH was essential for the accumulation of hTopBP1 on damaged DNA, where hTopBP1 interacts with hRad9, a component of the Rad9-Hus1-Rad1 complex. (biomedcentral.com)
  • It accomplishes these interactions with other protein partners through its breast cancer associated gene 1 C-terminus (BRCT) domains. (wikipedia.org)
  • Through its interactions with other proteins via its BRCT domains, hTopBP1 performs diverse functions [ 1 ]. (biomedcentral.com)
  • Knockdown of Rad9 in prostate tumor cells correlates with reduction of tumorigenicity in nude mice [ 16 ]. (biomedcentral.com)
  • Therefore, we suggest that the interaction between hMYH and hTopBP1 is crucial for activation of the ATR-mediated cell cycle checkpoint. (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)
  • To mediate these aspects of DNA repair, TOPBP1 was found to associate with Rad9, which forms a complex with Rad1 and Hus1, hereby termed the 9-1-1 DNA repair clamp. (wikipedia.org)
  • It is not clear whether Rad1, Rad9 and Hus1 also have distinct functional activities independent of the heterotrimeric form. (biomedcentral.com)
  • Several PAR-binding modules orchestrate the relocation of DDR-associated factors in addition to the accumulation of intrinsically disordered proteins through an intracellular liquid demixing mechanism 11 , 12 . (nature.com)
  • Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials. (bvsalud.org)
  • An alternatively spliced transcript variant of this gene has been reported, however, its full length nature is not known. (utsouthwestern.edu)
  • CTMP offers been shown to inhibit PKB/Akt activation NKP608 in the plasma membrane in response to numerous stimuli and also to have tumor suppressor-like functions. (tech-strategy.org)
  • and other important immune-response genes. (gsea-msigdb.org)
  • Our conclusions are that under stress conditions, the efficiency and capacity for DNA repair mediated by the ATM/RAD9 cell signaling network depend on the abundance of both proteins and that, in general, DNA repair network efficiencies are genotype-dependent and can vary within a specific range. (aacrjournals.org)
  • DNA topoisomerase 2-binding protein 1 (TOPBP1) is a scaffold protein that in humans is encoded by the TOPBP1 gene. (wikipedia.org)
  • This was supported by our finding that the levels of tricarboxylic Estrogen Receptor Pathway acid cycle intermediates change divergently upon hyper activation of Bcr Abl: the intracellular concentrations of fumarate and malate were increased whereas the citrate and isocitrate levels were decreased. (rafinhibitors.com)
  • hRad9 is a cell cycle checkpoint gene that is up-regulated in breast cancer. (biomedcentral.com)
  • Localisation of hRad9 protein were performed on paired tumor and normal breast tissues. (biomedcentral.com)
  • Increased hRad9 protein was observed in breast cancer cells nucleus compared to non-tumor epithelium. (biomedcentral.com)
  • This nuclear protein existed in hyperphosphorylated forms which may be those of the hRad9-hRad1-hHus1 complex. (biomedcentral.com)
  • Finding of hyperphosphorylated forms of hRad9 in the nucleus of cancer cells is in keeping with its function in ameliorating DNA instability, whereby it inadvertently assists tumor growth. (biomedcentral.com)
  • It also contains a nuclear localization sequence (NLS) that targets the hRad9 protein into the nucleus [ 11 ]. (biomedcentral.com)
  • Thus, in addition to its checkpoint control function, hRad9 may play a role in regulating apoptosis. (biomedcentral.com)
  • Besides the existence of 9-1-1 heterotrimer in K562 and 293 human cells, a significant amount of hRad1 also exists in monomeric form, but monomeric hRad9 and hHus1 were not detectable in a study by Karnitz's group [ 10 ] and in our unpublished experiments in 293 human cells. (biomedcentral.com)
  • We have previously shown that the mRNA up-regulation correlated with tumor size and local recurrence. (biomedcentral.com)
  • Another conclusion from most of the cases is that animals or cells haploinsufficient for the specified proteins have higher transformation rates after DNA damage is induced, but when their DNA is not significantly damaged by exogenous sources, tumor development rates are the same as for their wild-type counterparts. (aacrjournals.org)
  • Although DON turned out to be toxic in presence of imatinib, it significantly reduced imatinib withdrawal induced cell death. (rafinhibitors.com)
  • Keratinocytes isolated from Mrad1 +/- mice had significantly more spontaneous DNA double strand breaks, proliferated slower and had slightly enhanced spontaneous apoptosis than Mrad1 +/+ control cells. (biomedcentral.com)
  • Because the effect of haploinsufficiency for one protein is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes, critical for pathways that control DNA damage signaling, repair or apoptosis. (aacrjournals.org)
  • However, in established cancer cells, such DNA repair system may prevent further DNA damage in their progeny and decrease in apoptosis resulting in enhancement of tumor growth. (biomedcentral.com)
  • DNA damage caused by these genotoxins can be efficiently fixed by DNA repair in cooperation with cell cycle checkpoints. (biomedcentral.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)
  • a connection between mitochondrial function and dynamics in the legislation of fat burning capacity cell loss of life neurotransmission cell routine control and advancement [15]. (tech-strategy.org)
  • These genetic aberrations may cause loss of growth inhibition in normally quiescent cells and result in carcinogenesis [ 5 ]. (biomedcentral.com)
  • Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant and ubiquitous nuclear protein that uses NAD + to synthesize a multibranched polyanion composed of ADP-ribose moieties, giving rise to poly(ADP-ribose) (PAR), onto itself or a variety of target proteins. (nature.com)
  • On the contrary, enhanced glycolysis could be linked to the cell death observed 48 hours after imatinib withdrawal as inhibition of glycolysis by 2 deoxyglucose completely rescued cells from imatinib withdrawal induced death. (rafinhibitors.com)
  • A significant, although incomplete, inhibition of cell death was also observed upon partial deprivation of glutamine from the medium and inhibition Celastrol of glutaminase activity using the glutaminase inhibitor 6 diazo 5 oxo l norleucine. (rafinhibitors.com)
  • Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. (bvsalud.org)
  • Abcam is leading the way in addressing this with our range of recombinant monoclonal antibodies and knockout edited cell lines for gold-standard validation. (abcam.cn)
  • Changes in TOPBP1 gene expression are associated with pulmonary hypertension, breast cancer, glioblastoma, non-small cell lung cancer, and sarcomas. (wikipedia.org)
  • As the expression level of hTERT was similar in both cells, the result suggested that hTERT could be presumably phosphorylated by BCR ABL. (rafinhibitors.com)
  • Conversely the dynamin-related protein 1 (Drp1/DNM1) is definitely a cytosolic protein recruitment of which to the OMM from the anchored fission 1 protein (Fis1p/FIS1) adaptor initiates and settings the fission and distribution of mitochondria in cells [19]. (tech-strategy.org)
  • One would expect that this gene functions as a tumor suppressor gene. (biomedcentral.com)
  • To determine whether Rad1 functions to maintain genomic stability and prevent tumor development, we generated Mrad1 mutant mice by gene targeting. (biomedcentral.com)
  • The results show that cells having low levels of both ATM and RAD9 proteins are more sensitive to transformation by radiation, have different DNA double-strand break repair dynamics and are less apoptotic when compared with wild-type controls or those cells haploinsufficient for only one of these proteins. (aacrjournals.org)
  • These pairs are separated by a linker sequence that varies by protein. (wikipedia.org)
  • This result led us to consider that hTERT could be phosphorylated at tyrosine residues by BCR ABL in K562 cells. (rafinhibitors.com)
  • A concentrated localization of hTERT was observed in nucleoli of non treated K562 cells, but not in HL60 and Jurkat cells. (rafinhibitors.com)
  • Gleevec treatment induced dissociation of hTERT from nucleoli of K562 cells to nucleoplasm. (rafinhibitors.com)
  • These three cell lines were infected with GFPhTERT as the endogenous level of hTERT could not easily be detected in these cells by immunofluoresence microscopy. (rafinhibitors.com)