Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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 identification of breast cancer susceptibility genes, such as BRCA1, BRCA2, ATM, and p53, has been accompanied by the examination of the effects of radiation in combination with genetic mutations at these loci. Women at high risk for developing breast cancer may respond differently than the general population to low- and high-dose radiation exposures associated with screening and treatment. Epidemiologic studies are being performed to investigate the effects of radiation on subsequent breast cancer development in genetically predisposed individuals. Mouse strains with specific genetic modifications are being created to study the consequence of both inherited mutations and radiation on mammary gland carcinogenesis. Finally, studies investigating DNA damage-response pathways after radiation exposure are being performed. Recent work on the effects of several known or suspected breast cancer susceptibility genes, alone or in combination with radiation, is presented here, and directions for future research are considered.
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PMID:Breast cancer: genetic predisposition and exposure to radiation. 1055 88

Ataxia telangiectasia (AT) patients have inactivating mutations in both copies of the ATM gene. The ATM protein that the gene encodes is involved in DNA double-strand break (DSB) recognition; in its absence, p53 response to DSBs is delayed and reduced. In addition, AT patients have a high propensity for cancer, and cells from these patients show chromosomal instability. Here, using an in vivo mouse model system with the pink-eyed unstable mutation, we demonstrate that the absence of functional Atm results in a significantly elevated frequency of intrachromosomal recombination resulting in deletion events (wild-type 17.73%, heterozygous Atm 15.72%, and mutant Atm 30.33%). No such increase was observed in mice heterozygous for Atm. These results further advocate the role of ATM in maintaining genomic integrity after the onset of endogenous damage. This system relies on the initiation of events during a relatively short time frame to produce an observable deletion product. AT patients have a lifelong exposure to endogenous damage and perhaps similarly acting external agents. Because 25% of our genome consists of repeated elements, genomic instability due to an increased level of homologous recombination between such repeats, as observed here, may contribute to carcinogenesis in AT patients.
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PMID:Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice. 1066 93

Homozygous mutations of the gene mutated in ataxia telangiectasia (ATM) causes the AT syndrome, a pleiotropic phenotype that includes an increased risk of cancer. Most of the known mutations at the ATM gene lead to truncations which are usually associated with instability of mRNA and protein. A decrease or loss of ATM protein expression is associated with specific lymphoid malignancies in AT and non-AT patients. ATM is located within a region in chromosome 11q22-23 that is frequently undergoing loss of heterozygosity in sporadic breast cancer. Epidemiological studies estimated a 4-fold increase in breast cancer risk in heterozygous women. However, direct mutational analysis failed to clearly support a role for mutant ATM alleles in breast carcinogenesis. If ATM does have a suppressor role in this tissue, one would expect deficient ATM expression. We therefore tested the hypothesis that the expression of the ATM gene is reduced in sporadic breast cancer. We determined ATM transcript levels using competitive RT-PCR on 89 randomly selected sporadic breast cancer samples and 29 normal breast tissues. Of these, 11 were matched normal/cancer pairs. We also evaluated 7 breast cancer cell lines. Deficiency in ATM expression was not observed. Of the 11 matched pairs, 7 tumors expressed mildly higher levels, 3 tumors expressed the same amount and only 1 tumor expressed <50% of the normal match. In addition, 3 cancers with tumor-associated LOH of the ATM gene expressed higher mRNA levels in the tumors than in their normal tissue matches, suggesting that no correlation exists between tumors with LOH and decreased ATM expression. In summary, our results do not support a suppressor role for ATM in the development of sporadic breast cancer.
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PMID:Lack of defective expression of the ATM gene in sporadic breast cancer tissues and cell lines. 1071 53

Immunodeficiency, centromeric region instability, and facial anomalies (ICF), a rare recessive chromosome instability syndrome, involves the loss of DNA methyltransferase 3B activity and the consequent hypomethylation of a small portion of the genome. We demonstrate for the first time that ICF cells are strongly hypersensitive to a genotoxic agent, namely, ionizing radiation. However, unlike cell lines from patients with ataxia telangiectasia or Nijmegen breakage syndrome, chromosome instability syndromes also associated with unusual sensitivity to ionizing radiation, ICF cells did not show any deficiencies in their cell cycle checkpoints. ICF lymphoblastoid cell lines demonstrated increased apoptosis, long-term cell cycle arrest, and loss of viability in clonogenicity assays after irradiation compared to analogous normal cell lines. Also, the ICF cell lines were subject to high frequencies of rapid non-apoptotic cell death upon irradiation but not to abnormally high levels of radiation-induced, cytogenetically detectable chromosome abnormalities. ICF-associated undermethylation of some regulatory gene(s) might lead to an exaggerated response to radiation-induced breaks in DNA yielding increased rates of cell death and irreversible cell cycle arrest. As a defense against their frequent spontaneous breaks in chromosomes 1 and 16, ICF patients may be abnormally prone to chromosome break-induced apoptosis, non-apoptotic cell death, and permanent cell cycle arrest so as to minimize the number of cycling cells with spontaneous rearrangements. A similarly increased cell death and cycle-arrest response to chromosome breaks due to cancer-linked DNA hypomethylation might occur during carcinogenesis.
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PMID:Hypersensitivity to radiation-induced non-apoptotic and apoptotic death in cell lines from patients with the ICF chromosome instability syndrome. 1108 91

In search of functions involved in the regulation of gene amplification, and given the relevance of chromosome breakage in initiating the process, we analyzed the gene amplification ability of cells hypersensitive to inducers of DNA double-strand breaks and defective in cell cycle control: two human fibroblast strains derived from patients affected by ataxia telangiectasia (AT) and two hamster mutant cell lines belonging to complementation group XRCC8 of the rodent X-ray-sensitive mutants. These mutants are considered hamster models of AT cells. To measure gene amplification, the frequency and the rate of occurrence of N-(phosphonacetyl)-L-aspartate resistant cells were determined. In both hamster mutants, these two parameters were increased by about an order of magnitude compared with parental cells, suggesting that amplification ability was increased by the genetic defect. In primary AT fibroblasts, as in normal human fibroblasts, gene amplification was undetectable and a block in the G(1) phase of the cell cycle was induced upon PALA treatment. These results suggest that in AT fibroblasts, where only the ATM gene is mutated, ATM-independent mechanisms prevent gene amplification, while, in the immortalized hamster cell lines, which are already permissive for gene amplification, the AT-like defect increases the probability of gene amplification.
Carcinogenesis 2001 Jan
PMID:Gene amplification in fibroblasts from ataxia telangiectasia (AT) patients and in X-ray hypersensitive AT-like Chinese hamster mutants. 1115 52

The proteins encoded by BRCA1 and ATM may be important in DNA repair and maintenance of genomic integrity. Women heterozygous for a mutation in BRCA1 have an increased incidence of breast cancer. Some evidence also suggests that female carriers of ATM mutations may be susceptible to breast cancer. However, mice carrying one mutant allele of Brca1 or ATM are not highly susceptible to breast cancer. We proposed that heterozygosity for a mutant allele of Brca1 or ATM may confer a decreased ability to repair DNA damage. Such a defect might lead to a heightened sensitivity to tumor development in susceptible animal models. Therefore, mice predispose to mammary tumor development might show an increased susceptibility if they also carry an ATM or Brca1 mutation. C57BL/6J (B6) MIN/+ mice are predisposed to mammary and intestinal tumors and exposure to the point mutagen ethylnitrosourea (ENU) markedly increases mammary tumor multiplicity and incidence. To test our hypothesis, B6.MIN/+ male mice were crossed with 129S6/SvEvTac females heterozygous for a mutant allele of either Brca1 or ATM. Female progeny from each cross were treated with ENU and followed for tumor development. Only MIN/+ F1 females developed mammary tumors and heterozygosity for a mutant Brca1 or ATM allele had no effect on mammary or intestinal tumor incidence and multiplicity. These results suggest that heterozygosity for a mutation in Brca1 or ATM: does not affect MIN-induced tumorigenesis in mice under these conditions. Additionally, exposure to a somatic point mutagen does not increase tumor development in mice carrying Brca1 or ATM mutations.
Carcinogenesis 2001 Feb
PMID:Heterozygosity for a mutation in Brca1 or Atm does not increase susceptibility to ENU-induced mammary tumors in Apc(Min)/+ mice. 1118 58

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

Solar UVA, but not UVC, reaches the earth's surface and therefore is an important etiological factor for the induction of human skin cancer. ATM kinase is an important regulator of cell survival and cell cycle checkpoints. Here, we observe that UVA, unlike UVC, triggers ATM kinase activity, and the activation may occur through reactive oxygen species produced after irradiation of cells with UVA. We also show that ATM activation is involved in the apoptotic response to UVA but not UVC. Furthermore, we provide evidence that ATM-dependent p53 and c-Jun N-terminal kinase (JNK) pathways are linked to UVA-induced apoptosis. On the other hand, UVC-induced apoptosis occurs through ATR-dependent p53 phosphorylation as well as the JNK pathway. Therefore, these results suggest that ATM, like p53, is involved in the UVA-induced apoptosis to suppress carcinogenesis.
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PMID:Requirement of ATM in UVA-induced signaling and apoptosis. 1172 37

Balanced regulation of DNA double-strand break (DSB) repair is crucial for genetic integrity and cell survival. Cells perform DSB repair either by homologous recombination (HR) or by non-homologous end joining (NHEJ). Either option carries risk for DNA instability. The presence in the cell of the tumour suppressor p53 has been shown to suppress the levels of HR; however, the effect of p53 on DNA EJ is less well understood. Here we demonstrate dramatically increased DNA EJ activity in cell-free extracts from p53(-/-) mouse embryo fibroblasts (MEFs) compared with p53(+/+) MEFs. The addition of wild-type (wt) p53 to p53(-/-) MEFs extracts inhibited DNA EJ in a dose-dependent manner. Binding of wt p53 to DNA ends in vitro protected them from exonuclease attack and inhibited T4 DNA ligase-dependent EJ. This inhibitory effect was markedly enhanced for p53 R175H, a cancer-derived mutant of p53. In contrast, inhibition was negated in the presence of p53 S15D, a phosphorylation-mimicking mutant protein. Interestingly, p53 S15D stimulated in vitro DNA EJ of the blunt-ended DNA by T4 DNA ligase. Here we discuss the possibility that, in conjunction with its ability to control levels of HR, p53 may also serve to suppress DNA EJ in cells under normal conditions. This suppression may be associated with DNA-dependent protein kinases or ATM kinases, providing potential crosstalk between major cellular pathways of DNA repair and cell-cycle checkpoint mechanisms.
Carcinogenesis 2002 Apr
PMID:Effect of wild-type, S15D and R175H p53 proteins on DNA end joining in vitro: potential mechanism of DNA double-strand break repair modulation. 1196 Sep 5


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