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)

Ataxia-telangiectasia (AT) is an autosomally recessive human genetic disease with pleiotropic defects such as neurological degeneration, immunodeficiency, chromosomal instability, cancer susceptibility and premature aging. Cells derived from AT patients and ataxia-telangiectasia mutated (ATM)-deficient mice show slow growth in culture and premature senescence. ATM, which belongs to the PI3 kinase family along with DNA-PK, plays a major role in signaling the p53 response to DNA strand breaks. Telomere maintenance is perturbed in yeast strains lacking genes homologous to ATM and cells from patients with AT have short telomeres. We examined the length of individual telomeres in cells from ATM(-/-) mice by fluorescence in situ hybridization. Telomeres were extensively shortened in multiple tissues of ATM(-/-) mice. More than the expected number of telomere signals was observed in interphase nuclei of ATM(-/-) mouse fibroblasts. Signals corresponding to 5-25 kb of telomeric DNA that were not associated with chromosomes were also noticed in ATM(-/-) metaphase spreads. Extrachromosomal telomeric DNA was also detected in fibroblasts from AT patients and may represent fragmented telomeres or by-products of defective replication of telomeric DNA. These results suggest a role of ATM in telomere maintenance and replication, which may contribute to the poor growth of ATM(-/-) cells and increased tumor incidence in both AT patients and ATM(-/-) mice.
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PMID:Extra-chromosomal telomeric DNA in cells from Atm(-/-) mice and patients with ataxia-telangiectasia. 1118 76

The bacterial cytolethal distending toxin (CDT) triggers a G2/M cell cycle arrest in eukaryotic cells by inhibiting the CDC25C phosphatase-dependent CDK1 dephosphorylation and activation. We report that upon CDT treatment CDC25C is fully sequestered in the cytoplasmic compartment, an effect that is reminiscent of DNA damage-dependent checkpoint activation. We show that the checkpoint kinase CHK2, an upstream regulator of CDC25C, is phosphorylated and activated after CDT treatment. In contrast to what is observed with other DNA damaging agents, we demonstrate that the activation of CHK2 can only take place during S-phase. Use of wortmannin and caffeine suggests that this effect is not dependent on ATM but rather on another as yet unidentified PI3 kinase family member. These results confirm that the CDT is therefore responsible for specific genomic injuries that block cell proliferation by activating a cell cycle checkpoint.
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PMID:Study of the cytolethal distending toxin (CDT)-activated cell cycle checkpoint. Involvement of the CHK2 kinase. 1124 Jan 39

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder sharing a pleiotropic phenotype with ataxia-telangiectasia (A-T), including increased radiosensitivity and cancer disposition. Insulin-like growth factor I receptor (IGF-IR) expression is reportedly decreased in A-T cells, which is thought to contribute to its increased radiosensitivity. In this study, we investigated whether the same mechanism underlies the radiosensitivity of NBS cells. GM7166VA7 cells lacking NBS1 protein displayed a phenotype of increased radiosensitivity, while the introduction of NBS1 cDNA conferred radioresistance comparable to normal cells. IGF-IR expression levels were essentially the same among normal, NBS, and NBS1-complemented NBS cells. There was no significant difference between NBS and NBS1-complemented cells in activation of major downstream pathways of IGF-IR upon IGF-I stimulation, including phosphatidylinositol-3(') kinase (PI3-K) and mitogen-activated protein kinase (MAPK). Collectively, IGF-IR-related events are unlikely to be disrupted in NBS cells, and therefore, defects in IGF-IR signaling do not explain the increased radiosensitivity of NBS cells.
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PMID:Insulin-like growth factor I receptor is expressed at normal levels in Nijmegen breakage syndrome cells. 1214 27

Ultraviolet (UV) irradiation produces DNA photoproducts that are blocks to DNA replication by normal replicative polymerases. A specialized, damage-specific, distributive polymerase, Pol H or Pol h, that is the product of the hRad30A gene, is required for replication past these photoproducts. This polymerase is absent from XP variant (XP-V) cells that must employ other mechanisms to negotiate blocks to DNA replication. These mechanisms include the use of alternative polymerases or recombination between sister chromatids. Replication forks arrested by UV damage in virus transformed XP-V cells degrade into DNA double strand breaks that are sites for recombination, but in normal cells arrested forks may be protected from degradation by p53 protein. These breaks are sites for binding a protein complex, hMre11/hRad50/Nbs1, that colocalizes with H2AX and PCNA, and can be visualized as immunofluorescent foci. The protein complexes need phosphorylation to activate their DNA binding capacity. Incubation of UV irradiated XP-V cells with the irreversible kinase inhibitor wortmannin, however, increased the yield of Mre11 focus-positive cells. One interpretation of this observation is that two classes of kinases are involved after UV irradiation. One would be a wortmannin-resistant kinase that phosphorylates the Mre11 complex. The other would be a wortmannin-sensitive kinase that phosphorylates and activates the p53/large T in SV40 transformed XP-V cells. The sensitive class corresponds to the PI3-kinases of ATM, ATR, and DNA-PK, but the resistant class remains to be identified. Alternatively, the elevated yield of Mre11 foci positive cells following wortmannin treatment may reflect an overall perturbation to the signaling cascades regulated by wortmannin-sensitive PI3 related kinases. In this scenario, wortmannin could compromise damage inducible-signaling pathways that maintain the stability of stalled forks, resulting in a further destabilization of stalled forks that then degrade, with the formation of DNA double strand breaks.
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PMID:DNA replication arrest in XP variant cells after UV exposure is diverted into an Mre11-dependent recombination pathway by the kinase inhibitor wortmannin. 1245 48

We report cytologic and genetic data indicating that telomere dysfunction induces a DNA damage response in mammalian cells. Dysfunctional, uncapped telomeres, created through inhibition of TRF2, became associated with DNA damage response factors, such as 53BP1, gamma-H2AX, Rad17, ATM, and Mre11. We refer to the domain of telomere-associated DNA damage factors as a Telomere Dysfunction-Induced Focus (TIF). The accumulation of 53BP1 on uncapped telomeres was reduced in the presence of the PI3 kinase inhibitors caffeine and wortmannin, which affect ATM, ATR, and DNA-PK. By contrast, Mre11 TIFs were resistant to caffeine, consistent with previous findings on the Mre11 response to ionizing radiation. A-T cells had a diminished 53BP1 TIF response, indicating that the ATM kinase is a major transducer of this pathway. However, in the absence of ATM, TRF2 inhibition still induced TIFs and senescence, pointing to a second ATM-independent pathway. We conclude that the cellular response to telomere dysfunction is governed by proteins that also control the DNA damage response. TIFs represent a new tool for evaluating telomere status in normal and malignant cells suspected of harboring dysfunctional telomeres. Furthermore, induction of TIFs through TRF2 inhibition provides an opportunity to study the DNA damage response within the context of well-defined, physically marked lesions.
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PMID:DNA damage foci at dysfunctional telomeres. 1295 59

A critical pre-cytotoxic and -apoptotic DNA lesion induced by methylating carcinogens and chemotherapeutic drugs is O6-methylguanine (O6MeG). The mechanism by which O6MeG causes cell death via apoptosis is only partially understood. The current model ascribes a role to DNA replication and mismatch repair, which converts O6MeG into a critical distal lesion (presumably a DNA double-strand break) that is finally responsible for genotoxicity and apoptosis. Here we analysed whether the PI3-like kinase ATM is involved in this process. ATM is a major player in recognizing and signaling DNA breaks, but most reports are limited to ionizing radiation. Comparing mouse ATM knockout fibroblasts (ATM-/-) with the corresponding wild-type (ATM+/+) we show that ATM-/- cells are hypersensitive to the cytotoxic and apoptosis-inducing effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Inhibition of O6-methylguanine-DNA methyltransferase (MGMT) activity by O6-benzylguanine enhanced cell killing whereas the increase of MGMT activity by transfection with an expression vector provoked MNNG resistance. This was more pronounced in ATM-/- than in ATM+/+ cells, suggesting that O6MeG is responsible, at least in part, for increased MNNG sensitivity of ATM-/- cells. Cytogenetic studies showed that MNNG-induced sister-chromatid exchange frequencies were the same in ATM-/- and ATM+/+ cells in the first mitoses following treatment, but higher in ATM-/- cells than in the wild-type in the second post-treatment mitoses, when MGMT was depleted. Also, a significant higher frequency of MNNG-induced chromosomal aberrations was observed in ATM-/- than in ATM+/+ cells when analysed at a late recovery time, which is consistent with O6MeG being the inducing lesion. In summary, we conclude that ATM is not only involved in resistance to ionizing radiation but also to methylating agents, playing a role in the repair of secondary DNA damage generated from O6MeG lesions. The data also show that ATM is not required for activating the apoptotic pathway in response to O6MeG since ATM-/- cells are able to undergo apoptosis with high frequency.
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PMID:Loss of ATM sensitizes against O6-methylguanine triggered apoptosis, SCEs and chromosomal aberrations. 1501 Mar 11

Together with the Tel1 PI3 kinase, the Mre11/Rad50/Xrs2 (MRX) complex is involved in checkpoint activation in response to double-strand breaks (DSBs), a function also conserved in human cells by Mre11/Rad50/Nbs1 acting with ATM. It has been proposed that the yeast Tel1/MRX pathway is activated in the presence of DSBs that cannot be resected. The Mec1 PI3 kinase, by contrast, would be involved in detecting breaks that can be processed. The significance of a Mec1/MRX DSB-activated DNA damage checkpoint has yet to be reported. To understand whether the MRX complex works specifically with Tel1 or Mec1, we investigated MRX function in checkpoint activation in response to endonuclease-induced DSBs in synchronized cells. We found that the expression of EcoRI activated the G1 and intra-S phase checkpoints in a MRX- and Mec1-dependent, but Tel1-independent manner. The pathways identified here are therefore different from the Tel1/MRX pathway that was previously reported. Thus, our results demonstrate that MRX can function in concert with both Mec1 and Tel1 PI3K-like kinases to trigger checkpoint activation in response to DSBs. Importantly, we also describe a novel MRX-independent checkpoint that is activated in late S-phase when cells replicate their DNA in the presence of DSBs. The existence of this novel mode of checkpoint activation explains why several previous studies had reported that mutations in the MRX complex did not abrogate DSB-induced checkpoint activation in asynchronous cells.
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PMID:Double-strand breaks trigger MRX- and Mec1-dependent, but Tel1-independent, checkpoint activation. 1687 33

1. Activation of angiotensin II AT1 receptors (AT1R) stimulates catecholamine systems within both central and peripheral tissues that are associated with blood pressure control. In the present study, we sought to determine whether the hypertensive phenotype of the spontaneously hypertensive rat (SHR) is associated with changes in AT1R gene expression and whether gene expression of downstream signalling molecules was coupled to catecholamine gene expression, both in key brainstem nuclei and in peripheral sites implicated in cardiovascular control. 2. Gene expression levels of AT1R, extracellular signal-regulated kinase (ERK) 1 and 2 and phosphatidylinositol 3-kinase (PI3-K) were quantified in Wistar-Kyoto (WKY) rats and SHR. Messenger RNA expression levels were quantified using real time reverse transcription-polymerase chain reaction. In addition, we investigated whether there was a relationship between gene expression and systolic blood pressure. 3. The gene expression levels of AT1R, ERK2 and PI3-K were significantly higher in the paraventricular nucleus of the hypothalamus (4.12-, 1.40- and 1.38-fold, respectively), rostral ventrolateral medulla (2.71-, 1.33- and 2.73-fold, respectively), spinal cord (30.5-, 2.72- and 1.53-fold, respectively), adrenal medulla (1.68-, 1.55- and 1.76-fold, respectively) and coeliac ganglion (1.39-, 1.35- and 1.12-fold, respectively) in SHR compared with WKY rats. There was no significant difference in the level of ERK1 gene expression between the two strains. The gene expression levels of AT1R and ERK2 were positively correlated with blood pressure in all central nervous tissues investigated in the SHR, but not in WKY rats. Gene expression levels of the AT1R in the coeliac ganglion and adrenal medulla were also positively correlated with increased systolic blood pressure. 4. The present data suggest that a defect in AT1R expression (that may further alter downstream signalling pathways) in the SHR may be responsible, at least in part, for the hypertensive phenotype.
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PMID:Upregulation of angiotensin AT1 receptor and intracellular kinase gene expression in hypertensive rats. 1689 41

Cells that suffer substantial inhibition of DNA replication halt their cell cycle via a checkpoint response mediated by the PI3 kinases ATM and ATR. It is unclear how cells cope with milder replication insults, which are under the threshold for ATM and ATR activation. A third PI3 kinase, DNA-dependent protein kinase (DNA-PK), is also activated following replication inhibition, but the role DNA-PK might play in response to perturbed replication is unclear, since this kinase does not activate the signaling cascades involved in the S-phase checkpoint. Here we report that mild, transient drug-induced perturbation of DNA replication rapidly induced DNA breaks that promptly disappeared in cells that contained a functional DNA-PK whereas such breaks persisted in cells that were deficient in DNA-PK activity. After the initial transient burst of DNA breaks, cells with a functional DNA-PK did not halt replication and continued to synthesize DNA at a slow pace in the presence of replication inhibitors. In contrast, DNA-PK deficient cells subject to low levels of replication inhibition halted cell cycle progression via an ATR-mediated S-phase checkpoint. The ATM kinase was dispensable for the induction of the initial DNA breaks. These observations suggest that DNA-PK is involved in setting a high threshold for the ATR-Chk1-mediated S-phase checkpoint by promptly repairing DNA breaks that appear immediately following inhibition of DNA replication.
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PMID:DNA-PK is involved in repairing a transient surge of DNA breaks induced by deceleration of DNA replication. 1728 Jun 85

p53 is an important regulator of cell growth and apoptosis and its activity is regulated by phosphorylation. Accordingly, in neonatal rat cardiomyocytes we examined the involvement of p53 in H(2)O(2)-induced apoptosis. Treatment with 50-100 microM H(2)O(2) markedly induced apoptosis in cardiomyocytes, as assessed by gel electrophoresis of genomic DNA. To examine whether H(2)O(2) increases p53 phosphorylation in cardiomyocytes, we utilized an antibody that specifically recognizes phosphorylated p53 at serine-15. The level of phosphorylated p53 was markedly increased by 100 microM H(2)O(2) at 30 and 60 min. Using specific protein kinase inhibitors we examined the involvement of protein kinases in p53 phosphorylation in response to H(2)O(2) treatment. However, staurosporine, a broad spectrum inhibitor of protein kinases, SB202190, a specific p38 kinase inhibitor, PD98059, a MAP kinase inhibitor, wortmannin, an inhibitor of DNA-PK and PI3 kinase, SP600125, a JNK inhibitor and caffeine,an inhibitor of ATM and ATR, failed to prevent the H(2)O(2)-induced phosphorylation of p53. cDNA microarray revealed that H(2)O(2) markedly increased expression of several p53 upstream modifiers such as the p300 coactivator protein and several downstream effectors such as gadd45, but decreased the expression of MDM2, a negative regulator of p53. Our results suggest that phosphorylation of p53 at serine-15 may be an important signaling event in the H(2)O(2)-mediated apoptotic process.
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PMID:Oxidative stress enhances phosphorylation of p53 in neonatal rat cardiomyocytes. 1745 21


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