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)

Radiosensitivity is a major hallmark of the human genetic disorder ataxia telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vivo after exposure of patients to therapeutic doses of radiation and in cells in culture. Clearly an understanding of the nature of the molecular defect in ataxia telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas, the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia telangiectasia (A-T)? As outlined above, since radiosensitivity is a universal characteristic of A-T, understanding the mechanism of action of ATM will provide additional information on radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM-controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense cDNA constructs into tumours to achieve the same end-point.
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PMID:Radiosensitivity and oxidative signalling in ataxia telangiectasia: an update. 968 57

Ataxia-telangiectasia (A-T) is a multisystem recessive disease characterized by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency and increased risk of cancer. The ATM gene, responsible for A-T, was recently cloned at human chromosome band 11q22-23, a region of frequent alterations in childhood acute lymphoblastic leukaemia (ALL). Children with A-T frequently develop T-ALL. We investigated 18 T-ALL samples for ATM mutations and loss of heterozygosity (LOH) at the ATM locus. No mutations of ATM were found within the coding region in the 18 T-ALL samples, and LOH at the ATM locus was detected in three. The ATM gene appears to be an infrequently altered tumour suppressor gene in childhood T-ALL.
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PMID:The ATM gene and susceptibility to childhood T-cell acute lymphoblastic leukaemia. 982 31

The gene mutated in ataxia telangiectasia (ATM) has an established tumour suppressor role in breast cancer. ATM appears to be expressed in most normal cells, including breast epithelium, where it has been postulated to have a nuclear role in cell cycle regulation following DNA damage. However, ATM is not upregulated after DNA damage. In this study, we demonstrate an absence of immunohistologically detectable levels of ATM in the normally quiescent myoepithelial cells that line normal breast ducts. This contrasts dramatically with the significant expression of ATM in the proliferative myoepithelium of sclerosing adenosis (n = 7). This upregulation of ATM suggests that ATM expression is coupled to the proliferative status of the myoepithelium. Our results also indicate that there are factors other than ATM gene mutations that can dramatically influence ATM expression in the breast and that these factors should be considered for their possible implications in carcinogenesis.
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PMID:Upregulation of ATM in sclerosing adenosis of the breast. 989 51

Frequent allelic deletion at chromosome 11q22-q23.1 has been described in breast cancer and a number of other malignancies, suggesting putative tumour suppressor gene(s) within the approximately 8 Mb deleted region. In addition, we recently described another locus, at the 11q25-qter region, frequently deleted in breast cancer, suggesting additional tumour suppressor gene(s) in this approximately 2 Mb deleted region. An 11q YAC contig was accessed and three YACs, one containing the candidate gene ATM at 11q23.1, and two contiguous YACs (overlapping for approximately 400-600 kb) overlying most of the 11q25 deleted region, were retrofitted with a G418 resistance marker and transfected into murine A9 fibrosarcoma cells. Selected A9 transfectant clones (and control untransfected and 'irrelevant' alphoid YAC transfectant A9 clones) were assayed for in vivo tumorigenicity in athymic female Balb c-nu/nu mice. All the 11q YAC transfectant clones demonstrated significant tumour suppression compared to the control untransfected and 'irrelevant' YAC transfected A9 cells. These results define two discrete tumour suppressor loci on chromosome 11q by functional complementation, one to a approximately 1.2 Mb region on 11q23.1 (containing the ATM locus) and another to a approximately 400-600 kb subterminal region on 11q25-qter.
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PMID:11q23.1 and 11q25-qter YACs suppress tumour growth in vivo. 1002 21

The ataxia telangiectasia (A-T) gene, ATM, predisposes affected homozygotes to a wide range of malignancies. It has been suggested that this is a consequence of the genomic instability associated with the syndrome. The elevated risk of malignancy is not, however, observed among A-T heterozygotes (except, apparently, regarding breast cancer). In this report we describe results from the study of the rare sporadic disease, T cell prolymphocytic leukaemia (T-PLL). In all individuals tested, we observed that at least one ATM allele was disrupted by rearrangement, that in many cases both alleles were disrupted and that there were additional mutations, predominantly missense, that clustered toward the 3' end of the gene corresponding to the protein's phosphatidylinositol 3-kinase (PIK)-related domain. We conclude that the ATM gene can act as a tumour suppressor in the development of sporadic T-PLL. Our finding of a surfeit of mutations within ATM may reflect the involvement of the gene at more than one step in tumorigenesis. In particular, we suggest that the clustering of missense mutations may pertain to the late-onset character of both sporadic and A-T-related T-PLL, since the closest homologue of Atm protein is the yeast TEL1 protein that maintains telomere length. ATM inactivation may not be the initiating event in T-PLL tumorigenesis: prior mutation of another gene--perhaps TCL1 activation--may be obligate. This would explain the recessive character of T-PLL risk in A-T.
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PMID:The ataxia telangiectasia gene in familial and sporadic cancer. 1002 98

The characterization of the rare, radiation-sensitive and cancer-prone syndromes, ataxia telangiectasia and Nijmegen breakage syndrome, has demonstrated that genetic predisposition increases the risk of developing cancer after exposure to ionizing radiation (IR). Molecular analyses of these disorders provide valuable insights into the normal function of these two gene products in the cellular response to IR-induced DNA damage. Their contribution to a cellular radiosensitive phenotype and their role in sporadic cancers can now be fully assessed. For example, the gene ataxia telangiectasia mutated (ATM) has recently been shown to be a tumour suppressor gene in T-cell prolymphocytic leukaemia, and there is increasing evidence that individuals with one mutated ATM or Nijmegen breakage syndrome (NBS1) allele have an increased predisposition to cancer.
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PMID:Radiation, DNA damage and cancer. 1020 48

A Task Group of the ICRP Committee 1 (Radiation Effects) has reviewed relevant data with the objective of advising the Main Commission of the ICRP on the possible implications for radiological protection of emerging views on genetic susceptibility to cancer (Chapter 1). Chapter 2 considers DNA damage and its processing/repair after ionising radiation and serves principally to demonstrate that a few rare cancer-prone, human recessive genetic disorders show DNA repair deficiency and profound increases in radiosensitivity. Less dramatic changes in radiosensitivity are also apparent in a wider range of such disorders. The cellular mechanisms that underly the association between DNA damage processing and tumorigenesis are discussed. Chapter 3 reviews the mechanisms and genetics of solid tumours illustrating the ways in which mutations in proto-oncogenes, tumour suppressor genes together with those in DNA repair and cell cycle control genes can contribute to tumour development. Specific examples are given of how germ line mutation of such genes can predispose to familial cancer. It is judged that up to 5% of all solid tumours have a recognisable genetic component. Heritable organ-specific effects are most usual and cancers of the breast and colon tend to show the most obvious genetic components. Clearly discernible genetic effects are seen when rare dominant germ line mutations express strongly as familial cancer (high penetrance mutations), but the existence of perhaps less rare low penetrance mutations and gene-gene interactions are recognised but not well understood. Chapter 4 considers the mechanisms and genetics of lympho-haemopoietic tumours. Specific chromosomal translocations and proto-oncogene activation events are much more frequent in human leukaemia/lymphoma than in solid tumours. Genetic predisposition to leukaemia/lymphoma is found in a number of non-familial recessive genetic disorders of DNA processing and/or chromosomal instability. Familial manifestation of susceptibility to these tumours is, however, extremely rare. The genetic component, although poorly defined, is judged to be less than that of solid tumours and expressed largely in childhood. Chapter 5 reviews and discusses limited data that comment upon tumorigenic radiosensitivity in cancer-prone genetic conditions. From knowledge of the fundamental processes involved it is judged that in most, but not all, cases genetic susceptibility to spontaneous tumours will be accompanied by a greater-than-normal risk after radiation. A review of epidemiological, clinical and experimental data relevant to this issue suggests that although a wide range of different sensitivities may be involved, a factor of 10 increase in sensitivity broadly accords with the limited human data available. This interim judgement of a factor of 10 increase in radiation risk in such human genetic disorders is made for the purposes of illustrative modelling and calculation. In addition, specific attention is given to breast cancer risk in heterozygotes for the radiosensitive human disorder, ataxia-telangiectasia; this association, while in no way discounted, is judged to be less strong than that claimed by some. Chapter 6 discusses and develops computational modelling procedures that aim to describe the impact of genetic factors on radiation-tumorigenesis in human populations. Estimates of the prevalence of known cancer-prone genetic disorders are made but breast cancer susceptibility is used to illustrate the application of the model developed. The most important message to emerge from this work is that, even at an assumed high level of radiation sensitivity, the prevalence of familial (high penetrance) genetic disorders in the population is too low (<1%) for there to be a significant impact on risk in typical human populations. In principle, however, there is the potential for such impact in atypical inbred sub-populations where these mutations can be more common. (ABSTRACT TRUNCATED)
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PMID:Genetic susceptibility to cancer. ICRP publication 79. Approved by the Commission in May 1997. International Commission on Radiological Protection. 1040 27

Ataxia-telangiectasia mutated (ATM) is the product of the gene mutated in the human genetic disorder ataxia-telangeictasia (A-T). It is a 370 kDa protein that is a member of the phosphatidyl inositol 3-kinases superfamily. A-T cells and those derived from Atm-/- mice are characterized by hypersensitivity to ionizing radiation and defective cell cycle checkpoints. Defects are observed at all cell cycle checkpoints in A-T cells post-irradiation including the G1/S interface where ATM plays an important role in the activation of the tumour suppressor gene product p53. Activation leads to the induction of p21/WAF1, inhibition of cyclin-dependent kinase activity, failure to phosphorylate key substrates such as the retinoblastoma protein and consequently G1 arrest. ATM also plays an important role in the regulation and surveillance of meiotic progression. Absence of ATM gives rise to a spectrum of defects including immunodeficiency, neurodegeneration, radiosensitivity and cancer predisposition. It is clear that a better definition of the role of ATM in DNA damage recognition, cell cycle control and cell signalling may assist in the treatment of the progressive neurodegeneration in this syndrome.
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PMID:ATM: the product of the gene mutated in ataxia-telangiectasia. 1046 28

The long arm of chromosome 11 has received much scrutiny as a high frequency of deletions of various sites has been observed in different tumour types, indicating the presence of putative tumour suppressor genes. In the present study, 81 primary cervical carcinomas were examined for allelic imbalance (AI) using nine microsatellite markers, mapping to the chromosomal region 11q23.1 where the ATM gene is located. AI at any locus in the region was found in 34 of 81 (42%) tumours. AI frequencies varied from 12 to 31% for the different markers used, with the highest frequency at marker D11S1294. Based on the findings of 17 cases with restricted areas of deletions, four chromosomal regions of possible importance in cervical carcinomas could be distinguished. The first region is located between the markers D11S1325 and D11S1819, the second region between D11S2179 and D11S1294, the third region between D11S1778 and D11S1818 and the fourth region between D11S1818 and D11S1347. The second region may thus contain part of the ATM gene. No association between AI of any marker and histopathological or clinical parameters was seen. When comparing the AI findings of the different loci with TP53 protein overexpression, the only significant association found was with D11S2179 located within the ATM gene. The results indicate that a tumour suppressor gene (or genes) on chromosome 11q.23.1 may be involved in carcinogenesis of the cervix and the involvement of the ATM gene remains a possibility.
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PMID:Allelic imbalance at chromosome region 11q23 in cervical carcinomas. 1049 43

The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase ATM; recent results suggest ATM acts via the downstream kinase Chk2/hCds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20.
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PMID:How to activate p53. 1080 7


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