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)

Patients treated with conservative surgery and radiation therapy for early-stage breast cancer develop a contralateral breast cancer at a rate of approximately 0.75% per year. Ataxia-telangiectasia (AT) is an autosomal recessive disease that is characterized by increased sensitivity to ionizing radiation (IR) and cancer susceptibility. Epidemiologic studies have suggested that AT carriers, who comprise 1% of the population, may be at an increased risk for developing breast cancer, particularly after exposure to IR. To test this hypothesis, we analyzed blood samples from 57 patients who developed a contralateral breast cancer at least 6 months after completion of radiation therapy for an initial breast tumor. A cDNA-based truncation assay in yeast was used to test for heterozygous mutations in the ATM gene, which is responsible for AT. No mutations were detected. Our findings fail to support the hypothesis that AT carriers account for a significant fraction of breast cancer cases arising in women after exposure to radiation. Genes Chromosomes Cancer 27:124-129, 2000.
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PMID:Prevalence of germline truncating mutations in ATM in women with a second breast cancer after radiation therapy for a contralateral tumor. 1061 99

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

Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.
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PMID:Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice. 1146 22

Fanconi anaemia (FA) is a rare autosomal recessive disease characterized by increased spontaneous and DNA crosslinker-induced chromosome instability, progressive pancytopenia and cancer susceptibility. An increasing number of genes are involved in FA, including the breast cancer susceptibility gene BRCA2. Five of the FA proteins (FANCA, FANCC, FANCE, FANCF and FANCG) assemble in a complex that is required for FANCD2 activation in response to DNA crosslinks. Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci. FANCD2 is independently phosphorylated by ATM (the protein whose gene is mutated in ataxia telangiectasia) in response to ionizing radiation. In addition, the FA proteins are interconnected with other nuclear and cytoplasmic factors all related to cellular responses to carcinogenic stress and to caretaker and gatekeeper functions. In this review, the most recently published data on the molecular biology of the FA pathway and its molecular crosstalk with ATM, BRCA1 and BRCA2, proteins involved in xenobiotic and reactive oxygen species metabolism, apoptosis, cell cycle control and telomere stability, are summarized. The currently available data indicate that FA is a central node in a complex nuclear and cytoplasmic network of tumour suppressor and genome stability pathways fully committed to prevent cancer.
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PMID:The Fanconi anaemia genome stability and tumour suppressor network. 1243 50

Telomeres, functional complexes that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, which could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity.
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PMID:[Telomeres and genomic damage repair. Their implication in human pathology]. 1253 99

Ataxia telangiectasia is one of a group of recessive hereditary genomic instability disorders and is characterized by progressive neurodegeneration, immunodeficiency and cancer susceptibility. Heterozygotes for the mutated gene are more susceptible to cancer and to ischaemic heart disease. The affected gene, ATM (ataxia telangiectasia mutated), has been cloned and codes for a protein kinase (ATM), which orchestrates the cellular response to DNA double-strand breaks after ionising radiation. An underlying feature of ataxia telangiectasia is oxidative stress and there is chronic activation of stress response pathways in tissues showing pathology such as the cerebellum, but not in the cerebrum or liver. ATM has also been shown to be activated by insulin and to have a wider role in signal transduction and cell growth. Many, but not all, aspects of the phenotype can be attributed to a defective DNA damage response. The oxidative stress may result directly from accumulated DNA damage in affected tissues or ATM may have an additional role in sensing/modulating redox homeostasis. The basis for the observed tissue specificity of the oxidative damage in ataxia telangiectasia is not clear.
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PMID:Oxidative stress in ataxia telangiectasia. 1263 40

Fanconi anaemia (FA) is a rare disease characterized by chromosome instability and cancer susceptibility. With the exception of FANCD2, none of the Fanconi anaemia genes are conserved in evolution, limiting the study of the Fanconi anaemia pathway in genetically tractable models. Here we report the cloning and sequencing of a Drosophila full length cDNA homologous to human FANCD2 (dmFANCD2) as a first step in using Drosophila in Fanconi anaemia research. dmFANCD2 is composed of 14 exons coding for a protein of 1478 aminoacids. Southern blot and in situ hybridization analysis indicated that dmFANCD2 is present at single copy in the Drosophila genome and maps at the chromosomal band 92-F3. Sequence and structural biocomputational analysis indicated that, although the aminoacidic sequence, and specially the N-terminus region, is not highly conserved between humans and flies (23% identity and 43% similarity), both proteins are of the same size, globular and compact, with several transmembrane helixes and related to nuclear membrane proteins. Interestingly, the human ATM phosphorylation site at S222 and the complex-dependent monoubiquitination site at K561 are highly conserved in Drosophila at positions S267 and K595, respectively. The same is true for other putative ATM sites and their aminoacidic environment and for two out of three aminoacid mutations associated with human pathology. These results suggest that the key FANCD2 features have been conserved during over 500 million years of divergent evolution, highlighting their biological importance.
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PMID:Molecular cloning of the Drosophila Fanconi anaemia gene FANCD2 cDNA. 1276 53

Ataxia-telangiectasia (AT) is an autosomal recessive syndrome of combined immunodeficiency. Hallmarks of the disease comprise progressive cerebellar ataxia, oculocutaneous telangiectasia, cancer susceptibility and variable humoral and cellular immunodeficiency. We describe a patient with AT presenting with autoimmune haemolytic anaemia, neutropenia, hepatosplenomegaly, lymphadenopathy and hyper-IgM at the age of 6 months. At the age of 26 months she developed persistent fever, progressive lymphadenopathy and pulmonary nodular infiltrates, which were responsive to steroid therapy.
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PMID:Unusual and severe disease course in a child with ataxia-telangiectasia. 1291 15

Ataxia telangiectasia (A-T), an autosomal recessive neuro-immunologic disease with cancer susceptibility, results from ATM gene mutations. Most mutations in A-T patients cause protein truncation. Epidemiologic evidence suggests that ATM gene mutation carriers may be at increased risk for breast cancer, but the protein-truncating mutations that compose the majority of mutations in patients with ataxia telangiectasia are not elevated in women with breast cancer. In this report we present evidence that missense mutations in the ATM gene predispose to breast cancer. The analysis was performed in two phases in a total of 90 women with breast cancer and 90 ethnically similar control individuals. DOVAM-S, a robotically enhanced multiplexed, highly redundant form of SSCP in which virtually all mutations within the input amplicons can be detected, was used to scan all the coding exons and flanking splice junctions. Cohort-specific mutations were significantly elevated in women with breast cancer in phase 1 (43 cases) and phase 2 (47 cases). For the 90 patients and 90 controls, total missense mutations were significantly elevated in cases [OR=2.0; 90% CI=1.01-4.15]. Cohort-specific missense variants displayed an odds ratio of 4.0 (90% CI=1.37-13.5). It is estimated that the attributable risk of mutations in the ATM gene is 13% in this cohort of women with breast cancer.
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PMID:ATM missense mutations are frequent in patients with breast cancer. 1293 22

Ataxia-telangiectasia (A-T) is a syndrome of cancer susceptibility, immune dysfunction, and neurodegeneration that is caused by mutations in the A-T-mutated (ATM) gene. ATM has been implicated as a critical regulator of cellular responses to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although defective cell cycle-checkpoint regulation and associated genomic instability presumably contribute to cancer susceptibility in A-T, the mechanism of neurodegeneration in A-T is not well understood. In addition, although ATM is required for the induction of the p53 transcriptional program in response to DNA damage, the identities of the relevant transcription factors that mediate ATM-dependent changes in gene expression remain largely undetermined. In this article, we describe a signal transduction pathway linking ATM directly to the Ca(2+)/cAMP response element-binding protein, CREB, a transcription factor that regulates cell growth, homeostasis, and survival. ATM phosphorylated CREB in vitro and in vivo in response to ionizing radiation (IR) and H(2)O(2) on a stress-inducible domain. IR-induced phosphorylation of CREB correlated with a decrease in CREB transactivation potential and reduced interaction between CREB and its transcriptional coactivator, CREB-binding protein (CBP). A CREB mutant containing Ala substitutions at ATM phosphorylation sites displayed enhanced transactivation potential, resistance to inhibition by IR, and increased binding to CBP. We propose that ATM-mediated phosphorylation of CREB in response to DNA damage modulates CREB-dependent gene expression and that dysregulation of the ATM-CREB pathway may contribute to neurodegeneration in A-T.
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PMID:Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress. 1507 28


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