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)

In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Recently, however, deletion of the chromosomal region 11q22-q23 has been identified as a frequent event in this type of cancer, indicating the existence of a pathogenically relevant tumor suppressor gene in this region. The deleted segment contains the ATM (ataxia telangiectasia mutated) gene. ATM is an interesting candidate as a tumor suppressor gene because constitutive inactivation of the gene predisposes ataxia telangiectasia patients to lymphoid malignancies. To assess the potential involvement of the gene in MCL lymphomagenesis, we performed mutation analysis of ATM in 12 sporadic cases of MCL, 7 of them with a deletion of one ATM gene copy, by using single-strand conformation polymorphism analysis of reverse transcription-PCR-amplified mRNA and subsequent DNA sequencing. In all seven cases containing a deletion of one ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, truncation, or alteration of the protein. In addition, biallelic ATM mutations were identified in two MCLs that did not contain 11q deletions. Interestingly, in three cases analyzed, the ATM mutations detected in the tumor cells were not present in nonmalignant cells, demonstrating their somatic rather than germ-line origin. The inactivation of both alleles of the ATM gene by deletion and deleterious point mutation in the majority of cases analyzed indicates that ATM plays a role in the initiation and/or progression of MCL.
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PMID:Mantle cell lymphoma is characterized by inactivation of the ATM gene. 1070 20

ATM (ataxia telangiectasia mutated), the gene mutated in ataxia telangiectasia, is related to a family of large phosphatidylinositol 3-kinase domain-containing proteins involved in cell cycle control and DNA repair. We found that ATM(-/-) DT40 cells were more susceptible than wild-type cells to apoptosis induced not only by ionizing radiation and bleomycin but also by non-DNA-damaging apoptotic stimuli such as C(2)-ceramide. Furthermore, the apoptosis induced by C(2)-ceramide and H(2)O(2) was blocked by anti-oxidants, indicating that the ATM(-/-) DT40 cells had a heightened susceptibility to apoptosis induced by reactive oxygen intermediates (ROI), presumably due to defective ROI-detoxification activities. In support of this hypothesis, we found that more ROI were generated in ATM(-/-) DT40 cells than in wild-type cells, following treatment with the above apoptotic stimuli. These results indicate that ATM plays important roles in the maintenance of the cell homeostasis in response to oxidative damage.
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PMID:Protective roles for ATM in cellular response to oxidative stress. 1078 20

The mechanism(s) of c-Myc transcription factor-induced apoptosis is still obscure. The activation of c-Myc has been found to lead into the processing/activation of caspases (caspase-3), but the significance of this for the cell demise is debatable. Here we report that several targets of caspases (PKCdelta, MDM2, PARP, replication factor C, 70 kDa U1snRNP, fodrin and lamins) are cleaved during c-Myc-induced apoptosis in Rat-1 MycER cells, indicating an important role for caspases in the apoptotic process. We further found that the ATM (ataxia telangiectasia mutated)--protein is a novel key substrate of caspases. In in vitro assays, purified recombinant ATM protein was found to be cleaved by the effector caspases 3 and 7. The functional significance of the ATM cleavage is supported by the finding that ectopic expression of ATM protected in part against apoptosis. We also show that c-Myc-induced apoptosis involves loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria into the cytosol and subsequent processing of caspase-9. The cleavage of caspase-9 is, however, minimal and a much later event than the processing/activation of caspase-3, suggesting that it is not the apical caspase. Evidence is provided that there is, nevertheless, an upstream caspase(s) regulating the functions of caspase-3 and mitochondria. Additionally, it was found that p53 becomes upregulated, together with its transcriptional targets MDM2 and p21, upon c-Myc induction, but this occurs also at a later time than the activation of caspase-3.
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PMID:Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as a new target of caspases. 1082 87

The ATM (ataxia telangiectasia mutated) gene product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. The human ATM protein shows similarity to several yeast and mammalian proteins involved in meiotic recombination and cell cycle progression. Because of the homology of the human ATM gene to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in ATM could lead to defective telomere maintenance. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia (AT), influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in AT cells is due to altered interactions between the telomeres and the nuclear matrix. These interactions were examined in nuclear matrix halos prior to and after irradiation. A difference was observed in the ratio of soluble and matrix-associated telomeric DNA between cells derived from AT and normal individuals. Treatment with ionizing radiation affected the ratio of soluble and matrix-associated telomeric DNA only in the AT cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, such interactions were examined in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix seen in AT cells. Fibroblasts from AT individuals transfected with a wild-type ATM gene had corrected telomere-nuclear matrix interactions. In experiments designed to determine whether there is a link between the altered telomere-nuclear matrix interactions and defective telomere movement and clustering, a significant difference was observed in the ratio of soluble compared to matrix-associated telomeric DNA sequences in meiocytes of Atm(-/-) and control mice. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix and that alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene. This paper summarizes our recent publications on the influence of inactivation of ATM on the interaction of telomeres with nuclear matrix in somatic and germ cells.
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PMID:Influence of ATM function on interactions between telomeres and nuclear matrix. 1093 83

In yeast cells, the intra-S-phase checkpoint slows down the rate of DNA replication in response to DNA damage. Here we showed that a similar checkpoint mechanism is present and activated by anti-tumour drugs in HL-60 and Epstein-Barr virus (EBV)-transformed human lymphoblastoid cells. Using bromodeoxyuridine (BrdU) pulse labelling combined with two-dimensional flow cytometric analysis, we clearly visualized the cell-cycle progression of the BrdU-positive population (cells originally belonging to the S phase) and detected even subtle changes in S-phase progression induced by mild drug treatment conditions free of apoptosis. The DNA topoisomerase II inhibitors, doxorubicin and etoposide (250 nmol/l and 400 nmol/l, respectively, for 8 h), retained the BrdU-positive HL-60 cells in the latter half of S and G2/M positions, and the pyrimidine analogue anti-metabolite, cytosine beta-D-arabinofuranose (Ara-C; 50 nmol/l), kept them in early-to-late S phase after 8 h of incubation. Because 10 micromol/l of caffeine added 2 h later attenuated the S-phase retardation by these drugs in HL-60 cells, slowing of the S-phase progression should be actively regulated. Furthermore, two ataxia telangiectasia (AT)-derived lymphoblastoid cell lines were impaired in the doxorubicin-induced S-phase retardation, which indicated that the process is at least partially dependent on ataxia telangiectasia mutated (ATM) gene product. The inhibitory mechanism on S-phase progression elicited by anti-tumour drugs in HL-60 and lymphoblastoid cells may therefore correspond to the intra-S-phase checkpoint of the yeast cells.
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PMID:Activation of an ataxia telangiectasia mutation-dependent intra-S-phase checkpoint by anti-tumour drugs in HL-60 and human lymphoblastoid cells. 1105 63

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

483 Norwegian breast cancer patients were screened for six different ataxia telangiectasia mutated (ATM) mutations previously found to account for 83% of the disease alleles in Norwegian ataxia telangiectasia (AT) patients. Only one carrier was found. These results provide no evidence in favour of an excess risk of breast cancer associated with heterozygosity for classical AT mutations, but remain consistent with a maximum 2.4-fold increased risk.
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PMID:Screening breast cancer patients for Norwegian ATM mutations. 1110 61

p53 is required for the induction of a G(1) and/or G(2) irreversible arrest after gamma irradiation (IR), whereas blocked DNA replication causes a p53-independent S-phase arrest. We have examined the response to p53 when DNA synthesis is blocked by hydroxyurea (HU) or aphidicolin or when DNA is damaged by gamma IR. Similarly to gamma IR, blocked DNA synthesis induces high levels of phosphorylated nuclear p53. Surprisingly, several (but not all) p53 transcriptional targets that are rapidly induced by gamma IR are weakly or not induced when DNA replication is blocked. Moreover, the p53 response to gamma IR is inhibited by pretreatment of cells with HU or aphidicolin, suggesting that blocked DNA replication prevents p53 from being fully active as a transcription factor. HU-induced stabilization of p53 neither requires functional ATM (ataxia telangiectasia mutated), nor interferes with the gamma IR-dependent activation of the ATM kinase. Thus, stalled replication forks activate kinases that modify and stabilize p53, yet act downstream of ATM to impair p53 transcriptional activity. The ramifications of this novel regulation of p53 are discussed.
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PMID:p53 accumulates but is functionally impaired when DNA synthesis is blocked. 1115 42

Fission yeast Cds1 is phosphorylated and activated when DNA replication is interrupted by nucleotide starvation or DNA damage. Cds1 enforces the S-M checkpoint that couples mitosis (M) to the completion of DNA synthesis (S). Cds1 also controls replicational stress tolerance mechanisms. Cds1 is regulated by a group of proteins that includes Rad3, a kinase related to human checkpoint kinase ATM (ataxia telangiectasia mutated). ATM phosphorylates serine or threonine followed by glutamine (SQ or TQ). Here we show that in vitro, Rad3 and ATM phosphorylate the N-terminal domain of Cds1 at the motif T(11)Q(12). Substitution of threonine-11 with alanine (T11A) abolished Cds1 activation that occurs when DNA replication is inhibited by hydroxyurea (HU) treatment. The cds1-T11A mutant was profoundly sensitive to HU, although not quite as sensitive as a cds1(-) null mutant. Cds1(T11A) was unable to enforce the S-M checkpoint. These results strongly suggest that Rad3-dependent phosphorylation of Cds1 at threonine-11 is required for Cds1 activation and function.
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PMID:Threonine-11, phosphorylated by Rad3 and atm in vitro, is required for activation of fission yeast checkpoint kinase Cds1. 1131 65

Subpopulations that are genetically predisposed to radiation-induced cancer could have significant public health consequences. Individuals homozygous for null mutations at the ataxia telangiectasia gene are indeed highly radiosensitive, but their numbers are very small. Ataxia Telangiectasia heterozygotes (1-2% of the population) have been associated with somewhat increased radiosensitivity for some end points, but none directly related to carcinogenesis. Here, intralitter comparisons between wild-type mouse embryo fibroblasts and mouse embryo fibroblasts carrying ataxia telangiectasia mutated (ATM) null mutation indicate that the heterozygous cells are more sensitive to radiation oncogenesis than their normal, litter-matched, counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally-significant radiosensitive human subpopulation.
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PMID:Modest increased sensitivity to radiation oncogenesis in ATM heterozygous versus wild-type mammalian cells. 1147 3


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