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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eukaryotic cells control the initiation of DNA replication so that origins that have fired once in S phase do not fire a second time within the same cell cycle. Failure to exert this control leads to genetic instability. Here we investigate how rereplication is prevented in normal mammalian cells and how these mechanisms might be overcome during tumor progression. Overexpression of the replication initiation factors Cdt1 and Cdc6 along with cyclin A-cdk2 promotes rereplication in human cancer cells with inactive p53 but not in cells with functional p53. A subset of origins distributed throughout the genome refire within 2-4 hr of the first cycle of replication. Induction of rereplication activates p53 through the ATM/ATR/Chk2 DNA damage checkpoint pathways. p53 inhibits rereplication through the induction of the cdk2 inhibitor p21. Therefore, a p53-dependent checkpoint pathway is activated to suppress rereplication and promote genetic stability.
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PMID:A p53-dependent checkpoint pathway prevents rereplication. 1271 85

The ability of the conceptus to respond to genotoxic stress may be critical for normal development, particularly after exposure to genotoxic teratogens. Members of the phosphatidylinositol 3-kinase (PI3K) superfamily are involved in controlling cell cycle activity and maintaining genomic stability. The expression of PI3K family members ATM, ATR, and DNA-PKcs, and downstream genes p53, GADD45, and p21, was examined in the mid organogenesis rat conceptus in vivo on gestational days (GD) 10 through 12 and in vitro following exposure to genotoxic stress. ATM was the most highly expressed PI3K family member in both yolk sac and embryo proper, with transcript levels increasing ~fourfold in the embryo from GD 10 to 12. Transcript concentrations for ATR, DNA-PKcs, and downstream genes were low in both tissues; all genes had increased transcript levels exclusively in the GD 12 embryo. Transient oxidative stress, induced by short-term, in vitro embryo culture, had no effect on transcript levels in either tissue. Culture for 24 or 44 h significantly decreased ATM transcript levels in both embryo and yolk sac, but downstream genes were unaffected compared to GD-11 and -12 in vivo levels, respectively. Exposure to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated form of the nitrogen mustard cyclophosphamide (CPA), had no effect on transcript levels for any of the genes examined. Therefore, while transcripts for genotoxic stress-response genes are present in the mid organogenesis rat conceptus, their expression is not regulated by exposure in culture to either transient oxidative stress or a genotoxic alkylating agent. The inability of the conceptus to upregulate transcripts in response to insult may contribute to an increased susceptibility to stressors during organogenesis.
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PMID:Genotoxic stress response gene expression in the mid-organogenesis rat conceptus. 1273 Jun 23

The p21(WAF1/Cip1) gene plays a central role in cell cycle regulation. Here we show that topoisomerase II inhibitors, genistein and etoposide, induce p21(WAF1/Cip1) expression mainly in a p53-dependent manner in human lung cancer cell line A549. However, although p53 accumulated, p21(WAF1/Cip1) expression did not depend on the level of Ser15 phosphorylation of p53. Caffeine, an ataxia telangiectasia-mutated (ATM), and ATM- and Rad3-related kinase (ATR) inhibitor, abrogated genistein-induced p21(WAF1/Cip1) and largely blocked etoposide-induced p21(WAF1/Cip1) expression. Wortmannin, an ATM- and DNA-dependent protein kinase inhibitor, partially inhibited p21(WAF1/Cip1) expression induced by genistein and etoposide, whereas UCN-01, a Chk1 inhibitor, partially blocked etoposide, but not genistein-induced p21(WAF1/Cip1) expression. These data suggest that both genistein and etoposide induce p21(WAF1/Cip1) expression in a p53-dependent manner. Genistein appears to stimulate p21(WAF1/Cip1) expression through p53 via ATM, whereas etoposide may activate both ATM and ATR pathways. Our results suggest different mechanisms participate in genistein and etoposide induced p21(WAF1/Cip1) expression.
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PMID:P21 response to DNA damage induced by genistein and etoposide in human lung cancer cells. 1276 22

The tumour suppressor activity of p53 in vivo can be subject to pressure from the physiological stress of hypoxia and we report on the development of a cell system to define the p53-dependent stages in the adaptation of cells to hypoxia. p53(+/+) cells exposed to hypoxia exhibited a transient arrest in G2/M, but escaped from this checkpoint and entered a long-term G(0)/G(1) arrest. By contrast, isogenic p53-null cells exposed to hypoxic conditions exhibited a 6-10-fold higher level of apoptosis, suggesting that p53 acts as a survival factor under limiting oxygen concentrations. Surprisingly, hypoxia-dependent growth arrest in p53(+/+) cells did not result in either p21(WAF1) or HIF-1 protein stabilization, but rather promoted a significant decrease in Ser(392)-site phosphorylation at the CK2/FACT site. However, chemically induced anoxia induced Ser(392)-site phosphorylation as well as stabilization of both p53 and HIF-1 proteins. In contrast to hypoxia, 5-flourouracil (5-FU)-induced p53-dependent cell death correlated with enhanced Ser(392) phosphorylation of p53 and elevated p21(WAF1) protein levels. Hypoxia inhibited 5-FU-induced p53-dependent cell death and attenuated p53 phosphorylation at the ATM and CK2/FACT phosphorylation sites. Although anoxia activates the p53 response, hypoxia silences the p53 transactivation pathway and identifies a physiological signalling model to study mechanisms of p53 inactivation under hypoxic conditions.
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PMID:Hypoxia attenuates the p53 response to cellular damage. 1277 95

Histone deacetylase (HDAC) inhibitors are known to induce expression of genes such as p21(WAF1), thereby, leading to cell cycle arrest. In this work, we show that p21(WAF1) induction by HDAC inhibitors (depsipeptide and trichostatin A) is defective in Ataxia telangiectasia (AT) cells but normal in matched wild-type (WT) cells (human diploid fibroblasts). To verify the role of ATM in this effect, we show that ectopic expression of the WT ATM gene in an AT cell line fully restores p21(WAF1) induction by the HDAC inhibitors. Furthermore, because caffeine and wortmannin attenuate p21(WAF1) induction in WT cells, it is probable that the phosphatidylinositol 3'-kinase activity is essential for this process. Besides the p21(WAF1) promoter, activation of topoisomerase IIIalpha and SV40 promoters by the HDAC inhibitors are also decreased in the AT cell lines relative to WT cells; thus, these findings pertain to other promoters. Finally, despite the obvious induction deficiency of gene expression, the overall levels of H3 and H4 histone acetylation appear to be the same between AT and normal cells in response to HDAC inhibitor treatments. Taken together, the data indicate that ATM is involved in histone acetylation-mediated gene regulation.
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PMID:Histone deacetylase inhibitors activate p21(WAF1) expression via ATM. 1278 95

p19ARF is induced in response to oncogene activation or during cellular senescence in mouse embryo fibroblasts, triggering p53-dependent and p53-independent cell cycle arrest and apoptosis. We have studied the involvement of human p14ARF as a regulator of p53 activity in normal human skin fibroblasts (NHFs) or WI38 lung embryonic fibroblasts expressing conditional Myc or E2F1 estrogen receptor fusion proteins. Both Myc and E2F1 activation rapidly induced p53 phosphorylation at Ser-15, p53 protein accumulation, and upregulation of the p53 target genes MDM2 and p21. Activation of E2F1 induced p14ARF mRNA and protein levels. In contrast, Myc activation did not induce any significant increase in p14ARF mRNA or protein levels in neither NHFs nor WI38 fibroblasts within 48 h. Myc and E2F1 induced p53 and cell cycle arrest even after silencing of p14ARF using short-interfering RNA. Treatment with the ATM/ATR kinase inhibitor caffeine prevented p53 accumulation upon activation of Myc or E2F1. Our results indicate that p53 phosphorylation, but not p14ARF, plays a major role for the induction of p53 in response to Myc and E2F1 activation in normal human fibroblasts.
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PMID:Myc and E2F1 induce p53 through p14ARF-independent mechanisms in human fibroblasts. 1290 82

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.
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PMID:Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways. 1291 35

We investigated the effects of metabolic labeling with [(3)H]thymidine, [(3)H]uridine, and [(14)C]thymidine on human cells in terms of cell growth, p53 signaling, and nucleotide excision repair. Labeling with [(3)H] nucleosides resulted in growth inhibition by both p53-dependent and -independent mechanisms. Tritium labeling also led to nuclear accumulation of p53 and induction of the p53-regulated gene p21(WAF1) and its encoded protein (p21). ATM-deficient cells, however, did not increase their p53 and p21 protein levels in response to radiolabeling. Thus, labeling of human cells with tritiated nucleosides activates the radiation-responsive, ATM-dependent, DNA-damage surveillance network. Labeling of normal cells with [(3)H]thymidine significantly accelerated the repair of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers, as monitored by a sensitive immunofluorescence assay. Unlike [(3)H] labeling, [(14)C] labeling did not produce any impact on proliferation, p53 signaling, or DNA repair. In the light of these findings, the validity of results obtained with nucleic acid synthesis and DNA repair assays that involve [(3)H] and [(14)C] labeling is discussed. Our immunofluorescence approach detected pyrimidine dimers after exposure to UV fluences as low as 1 J/m(2) (the lowest fluence examined). This approach may prove particularly useful for monitoring DNA damage and its repair following exposure to extremely low levels of genotoxic agents.
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PMID:Metabolic labeling of human cells with tritiated nucleosides results in activation of the ATM-dependent p53 signaling pathway and acceleration of DNA repair. 1294 3

We demonstrated that enhancement of X-ray-induced apoptosis/rapid cell death by wortmannin accompanied by increased activation of JNK/SAPK in human leukemia MOLT-4 cells. Rapid cell death/apoptosis was determined either by the dye exclusion test or by the appearance of Annexin V-positive cells and cleaved PARP fragments. Enhancement was observed only at higher concentrations of wortmannin, i.e. 1 microM or more. At these high concentrations, both DNA-PK and ATM were inhibited. X-ray-induced phosphorylation of Ser 15 of p53/TP53, accumulation of both p53/TP53 and p21/WAF1/CDKN1A, and phosphorylation of XRCC4 were all suppressed. The enhancement of apoptosis/rapid cell death by wortmannin was prevented by addition of caspase inhibitors, Z-VAD-FMK or Ac-DEVD-CHO, or by transfection and overexpression of mouse Bcl2, which is known as an anti-apoptosis protein. The requirement for a high concentration of wortmannin, i.e. 1 microM or more, indicates that inhibition of both DNA-PK and ATM was necessary for the enhanced apoptosis/rapid cell death. Phosphorylation of AKT/PKB was completely suppressed at a much lower concentration, i.e. 0.1 microM wortmannin, where no enhancement of X-ray-induced apoptosis/rapid cell death was observed. On the other hand, X-ray-induced phosphorylation of JNK and its kinase activity as well as apoptosis/rapid cell death were all significantly enhanced only at high concentrations of wortmannin, i.e. 1 microM or more. Furthermore, the extent of enhancement of both JNK phosphorylation and of apoptosis/rapid cell death by wortmannin was less in Rh1a cells, which are ceramide- and radiation-resistant variant cells compared to the parental MOLT-4 cells. Therefore, activation of the JNK pathway was considered important for the enhancement of X-ray-induced apoptosis/rapid cell death of MOLT-4 cells by wortmannin, because of the requirement for a higher concentration of wortmannin than that required for inhibition of AKT phosphorylation. The suppression of the AKT-dependent pathway by wortmannin may have some underlying role in activating the JNK pathway toward the enhancement of cell death in the current system.
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PMID:Wortmannin-enhanced X-ray-induced apoptosis of human T-cell leukemia MOLT-4 cells possibly through the JNK/SAPK pathway. 1296 28

In addition to replicative senescence, normal diploid fibroblasts undergo stress-induced premature senescence (SIPS) in response to DNA damage caused by oxidative stress or ionizing radiation (IR). SIPS is not prevented by telomere elongation, indicating that, unlike replicative senescence, it is triggered by nonspecific genome-wide DNA damage rather than by telomere shortening. ATM, the product of the gene mutated in individuals with ataxia telangiectasia (AT), plays a central role in cell cycle arrest in response to DNA damage. Whether ATM also mediates signaling that leads to SIPS was investigated with the use of normal and AT fibroblasts stably transfected with an expression vector for the catalytic subunit of human telomerase (hTERT). Expression of hTERT in AT fibroblasts resulted in telomere elongation and prevented premature replicative senescence, but it did not rescue the defect in G(1) checkpoint activation or the hypersensitivity of the cells to IR. Despite these remaining defects in the DNA damage response, hTERT-expressing AT fibroblasts exhibited characteristics of senescence on exposure to IR or H(2)O(2) in such a manner that triggers SIPS in normal fibroblasts. These characteristics included the adoption of an enlarged and flattened morphology, positive staining for senescence-associated beta-galactosidase activity, termination of DNA synthesis, and accumulation of p53, p21(WAF1), and p16(INK4A). The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which mediates signaling that leads to senescence, was also detected in both IR- or H(2)O(2)-treated AT and normal fibroblasts expressing hTERT. These results suggest that the ATM-dependent signaling pathway triggered by DNA damage is dispensable for activation of p38 MAPK and SIPS in response to IR or oxidative stress.
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PMID:Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts. 1457 Aug 74


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