Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic compounds are potent human carcinogens. Accumulated evidence has shown that arsenite-induced cytogenetic alterations are associated with the carcinogenicity of arsenic. Because p53 plays a guarding role in maintaining genome integrity and accuracy of chromosome segregation, the mechanistic effects of arsenite on p53 activation were analyzed. In the present study, arsenite-induced DNA strand breaks were confirmed by alkaline single-cell gel electrophoresis (comet assay) in human fibroblast (HFW) cells. Accompanying the appearance of DNA strand breaks was a significant accumulation of p53 in arsenite-treated HFW cells, as demonstrated by immunoblotting and immunofluorescence techniques. p53 downstream proteins, such as p21 and the human homologue of murine double minute-2, were also significantly induced by arsenite treatment. Cell cycle retardation and G2-M arrest were observed in 5-bromo-2'-deoxyuridine pulse-labeled HFW cells by flow cytometry. Wortmannin, an inhibitor of phosphatidylinositol 3-kinases, inhibited arsenite- or X-ray irradiation-induced p53 accumulation but did not alter UV irradiation- or N-acetyl-Leu-Leu-norleucinal-induced p53 accumulation. p53 phosphorylation on serine 15 was also confirmed by immunoblotting technique in arsenite- and X-ray-treated HFW cells but was not observed in UV- or N-acetyl-Leu-Leu-norleucinal-treated HFW cells. These results suggest the involvement of a phosphatidylinositol 3-kinase-related protein kinase in arsenite-induced p53 accumulation. For confirmation, we demonstrated that arsenite treatment, similar to X-ray irradiation, did not induce p53 accumulation in GM3395 fibroblasts derived from a patient with ataxia telangiectasia. In contrast, UV irradiation did cause p53 accumulation in these cells. Together, these findings infer that arsenite-induced DNA strand breaks may lead to p53 phosphorylation and accumulation through an ataxia telangiectasia mutated-dependent pathway in HFW cells.
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PMID:Arsenite induces p53 accumulation through an ATM-dependent pathway in human fibroblasts. 1110 96

ATR, a human phosphatidylinositol 3-kinase-related kinase, is an important component of the cellular response to DNA damage. In the present study, we evaluated the role of ATR in modulating the response of cells to S phase-associated DNA double-stranded breaks induced by topoisomerase poisons. Prolonged exposure to low doses of the topoisomerase I poison topotecan (TPT) resulted in S phase slowing because of diminished DNA synthesis at late-firing replicons. In contrast, brief TPT exposure, as well as prolonged exposure to the topoisomerase II poison etoposide, resulted in subsequent G(2) arrest. These responses were associated with phosphorylation of the checkpoint kinase Chk1. The cell cycle responses and phosphorylation of Chk1 were markedly diminished by forced overexpression of a dominant negative, kinase-inactive allele of ATR. In contrast, deficiency of the related kinase ATM had no effect on these events. The loss of ATR-dependent checkpoint function sensitized GM847 human fibroblasts to the cytotoxic effects of the topoisomerase I poisons TPT and 7-ethyl-10-hydroxycamptothecin, as assessed by inhibition of colony formation, increased trypan blue uptake, and development of apoptotic morphological changes. Expression of kdATR also sensitized GM847 cells to the cytotoxic effects of prolonged low dose etoposide and doxorubicin, albeit to a smaller extent. Collectively, these results not only suggest that ATR is important in responding to the replication-associated DNA damage from topoisomerase poisons, but also support the view that ATM and ATR have unique roles in activating the downstream kinases that participate in cell cycle checkpoints.
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PMID:S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. 1170 Mar 2

Rad17, Rad1, Hus1, and Rad9 are key participants in checkpoint signaling pathways that block cell cycle progression in response to genotoxins. Biochemical and molecular modeling data predict that Rad9, Hus1, and Rad1 form a heterotrimeric complex, dubbed 9-1-1, which is loaded onto chromatin by a complex of Rad17 and the four small replication factor C (RFC) subunits (Rad17-RFC) in response to DNA damage. It is unclear what checkpoint proteins or checkpoint signaling events regulate the association of the 9-1-1 complex with DNA. Here we show that genotoxin-induced chromatin binding of 9-1-1 does not require the Rad9-inducible phosphorylation site (Ser-272). Although we found that Rad9 undergoes an additional phosphatidylinositol 3-kinase-related kinase (PIKK)-dependent posttranslational modification, we also show that genotoxin-triggered 9-1-1 chromatin binding does not depend on the catalytic activity of the PIKKs ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), or DNA-PK. Additionally, 9-1-1 chromatin binding does not require DNA replication, suggesting that the complex can be loaded onto DNA in response to DNA structures other than stalled DNA replication forks. Collectively, these studies demonstrate that 9-1-1 chromatin binding is a proximal event in the checkpoint signaling cascade.
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PMID:Genotoxin-induced Rad9-Hus1-Rad1 (9-1-1) chromatin association is an early checkpoint signaling event. 1222 48

Members of the PI 3-kinase-related kinase (PIKK) family function in mitogenic and stress-induced signaling pathways in eukaryotic cells. Here, we characterize the newest PIKK family member, hSMG-1, as a genotoxic stress-activated protein kinase that displays some functional overlap with the related kinase, ATM, in human cells. Both ATM and hSMG-1 phosphorylate Ser/Thr-Gln-containing target sequences in the checkpoint protein p53 and the nonsense-mediated mRNA decay (NMD) protein hUpf1. Expression of hSMG-1 is required for optimal p53 activation after cellular exposure to genotoxic stress, and depletion of hSMG-1 leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). Moreover, IR exposure triggers hUpf1 phosphorylation at Ser/Thr-Gln motifs, and both ATM and hSMG-1 contribute to these phosphorylation events. Finally, NMD is suppressed in hSMG-1- but not ATM-deficient cells. These results indicate that hSMG-1 plays important roles in the maintenance of both genome and transcriptome integrity in human cells.
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PMID:The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells. 1517 54

Members of the phosphoinositide-3-kinase-related kinase (PIKK) family, which includes mTOR, ATM, ATR, and hSMG-1, play important roles in regulating the cellular response to environmental stimuli. Despite the similarity of their catalytic domain to that of phosphoinositide-3-kinase, these extremely large (>250 kDa) polypeptides function as serine/threonine protein kinases. The catalytic activities of these PIKK family members can now be measured in immune-complex kinase assays. This assay involves isolation of the kinase by immunoprecipitation and the in vitro phosphorylation of a specific substrate in the presence of radio-labeled ATP. Here we describe, in detail, the determination of PIKK catalytic activity with a standardized immune-complex kinase assay protocol.
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PMID:Determination of the catalytic activities of mTOR and other members of the phosphoinositide-3-kinase-related kinase family. 1522 May 25

The phosphoinositide 3-kinase related kinases (PIKKs) comprise a family of high molecular mass signaling proteins that play central roles in the control of cell growth, gene expression, and genome surveillance and repair in eukaryotic cells. Mammalian cells express six PIKK family members, five of which-ATM, ATR, mTOR, DNA-PK, and hSMG-1-function as protein serine-threosine kinases. This overview provides some general insights into the pharmacology, biochemistry, and function of this nonconventional group of protein kinases.
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PMID:PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. 1527 73

Recent studies have identified, hSMG-1 as the newest member of the phosphoinositide 3-kinase(PI3-kinase)-related kinase (PIKK) family. The protein kinase activity of hSMG-1 resembles that of the related PIKK, ATM, both in terms of substrate specificity and its sensitivity to inhibition by the fungal metabolite wortmannin. hSMG-1 is the ortholog of a Caenorhabditis elegans protein, CeSMG-1, which has been genetically linked to a critical mRNA surveillance pathway termed nonsense-mediated decay (NMD). The function of NMD is to mark for rapid degradation mRNAs that bear a premature termination codon. Compelling evidence now indicates that hSMG-1 is also a central player in the NMD pathway in human cells. In addition, hSMG-1, like ATM, appears to be involved in the recognition and/or repair of damaged DNA in these cells. In this review, we introduce a model in which hSMG-1 teams with ATM and ATR to insure the overall quality of the transcriptome in human cells.
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PMID:The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathways. 1527 77

Previous reports have suggested a connection between reduced levels of the catalytic subunit of DNA-dependent protein kinases (DNA-PKcs), a component of the nonhomologous DNA double-strand breaks end-joining system, and a reduction in ATM. We studied this possible connection in other DNA-PKcs-deficient cell types, and following knockdown of DNA-PKcs with small interfering RNA, Chinese hamster ovary V3 cells, lacking DNA-PKcs, had reduced levels of ATM and hSMG-1, but both were restored after transfection with PRKDC. Atm levels were also reduced in murine scid cells. Reduction of ATM in a human glioma cell line lacking DNA-PKcs was accompanied by defective signaling through downstream substrates, post-irradiation. A large reduction of DNA-PKcs was achieved in normal human fibroblasts after transfection with two DNA-PKcs small interfering RNA sequences. This was accompanied by a reduction in ATM. These data were confirmed using immunocytochemical detection of the proteins. Within hours after transfection, a decline in PRKDC mRNA was seen, followed by a more gradual decline in DNA-PKcs protein beginning 1 day after transfection. No change in ATM mRNA was observed for 2 days post-transfection. Only after the DNA-PKcs reduction occurred was a reduction in ATM mRNA observed, beginning 2 days post-transfection. The amount of ATM began to decline, starting about 3 days post-treatment, then it declined to levels comparable to DNA-PKcs. Both proteins returned to normal levels at later times. These data illustrate a potentially important cross-regulation between the nonhomologous end-joining system for rejoining of DNA double-strand breaks and the ATM-dependent damage response network of pathways, both of which operate to maintain the integrity of the genome.
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PMID:Deficiency in the catalytic subunit of DNA-dependent protein kinase causes down-regulation of ATM. 1575 61

We previously demonstrated that the nitroxide antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) increased latency to tumorigenesis and doubled (100%) the lifespan of Atm-deficient mice, a mouse model of ataxia telangiectasia, which displays accelerated oxidative damage and stress. Tempol treatment of cancer-prone p53-deficient mice resulted in a small but significant (25%) increase in lifespan by prolonging latency to tumorigenesis, demonstrating that existing oxidative stress and damage are not necessary for the chemopreventative effects of tempol. However, the relatively small effect on latency in p53-deficient mice and the finding that tempol-mediated resistance to oxidative insult was p53-dependent suggested a more direct role of p53 in the chemopreventative effects of tempol. Surprisingly, tempol treatment specifically increased serine 18 phosphorylation of p53 (but not gamma-H2AX) and p21 expression in primary thymocytes in vitro in a p53-dependent fashion. Inhibition of phosphoinositide 3-kinase (PI3K) family members suggested that SMG-1 was responsible for the tempol-mediated enhancement of p53 serine 18 phosphorylation. These data suggest that the chemopreventative effect of tempol is not solely due to the reduction of oxidative stress and damage but may also be related to redox-mediated signaling functions that include p53 pathway activation.
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PMID:Cancer chemoprevention by the antioxidant tempol acts partially via the p53 tumor suppressor. 1588 86

Members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, including the ATM, DNA-PKcs, Atr, and Trrap proteins, function in signal transduction pathways that activate the DNA damage response. PIKK proteins contain a conserved C-terminal FAT/kinase domain/FATC domain structure. The FATC domain of ATM mediates the interaction between ATM and Tip60, a histone acetyltransferase that regulates activation of ATM. Here, we examined whether the FATC domains of DNA-PKcs, Atr, and Trrap were also able to interact with Tip60. Deletion of the FATC domain of ATM blocked the interaction between ATM and Tip60 and suppressed the activation of ATM kinase activity by DNA damage. Replacement of the FATC domain of ATM with the FATC domains of DNA-PKcs, Atr, or Trrap restored the activation of ATM and its association with Tip60. These results indicate that the FATC domains of DNA-PKcs, Atr, Trrap, and ATM are functionally equivalent. Immunoprecipitation experiments demonstrated that Tip60 is constitutively associated with DNA-PKcs and that the histone acetyltransferase activity associated with DNA-PKcs is up-regulated by DNA damage. When Tip60 expression was suppressed by small interfering RNA, the activation of DNA-PKcs (measured by autophosphorylation of DNA-PKcs at serine 2056 and threonine 2609) was inhibited, demonstrating a key role for Tip60 in the activation of DNA-PKcs by DNA damage. The conserved FATC domain of PIKK proteins may therefore function as a binding domain for the Tip60 histone acetyltransferase. Further, the ability of Tip60 to regulate the activation of both ATM and DNA-PKcs in response to DNA damage demonstrates that Tip60 is a key component of the DNA damage-signaling network.
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PMID:The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM. 1660 69


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