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)

We report the p35 and p60 forms of XRCC4 protein, appearing in human leukemia MOLT-4 or U937 cells following X-irradiation or hyperthermia. p35 appeared in conjunction with the cleavage of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and the fragmentation of internucleosomal DNA, and was suppressed by Ac-DEVD-CHO. p35 was also produced in vitro by treating MOLT-4 cell lysate with recombinant caspases, suggesting that p35 was a caspase-cleaved fragment of XRCC4 in apoptotic cell death. p60 was sensitive to treatment with phosphatase or wortmannin and was undetectable in M059J cells deficient in DNA-PKcs. However, p60 was found in ataxia-telangiectasia cells after irradiation. These results indicated p60 as a phosphorylated form of XRCC4, requiring DNA-PKcs but not ataxia-telangiectasia mutated (ATM).
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PMID:Cleavage and phosphorylation of XRCC4 protein induced by X-irradiation. 1092 71

The Mre11 complex has been implicated in diverse aspects of the cellular response to DNA damage. We used in situ fractionation of human fibroblasts to carry out cytologic analysis of Mre11 complex proteins in the double-strand break (DSB) response. In situ fractionation removes most nucleoplasmic protein, permitting immunofluorescent localization of proteins that become more avidly bound to nuclear structures after induction of DNA damage. We found that a fraction of the Mre11 complex was bound to promyelocyte leukemia protein bodies in undamaged cells. Within 10 min after gamma irradiation, nuclear retention of the Mre11 complex in small granular foci was observed and persisted until 2 h postirradiation. In light of the previous demonstration that the Mre11 complex associated with ionizing radiation (IR)-induced DSBs, we infer that the protein retained under these conditions was associated with DNA damage. We also observed increased retention of Rad51 following IR treatment, although IR induced Rad51 foci were distinct from Mre11 foci. The ATM kinase, which phosphorylates Nbs1 during activation of the S-phase checkpoint, was not required for the Mre11 complex to associate with DNA damage. These data suggest that the functions of the Mre11 complex in the DSB response are implicitly dependent upon its ability to detect DNA damage.
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PMID:DNA damage-dependent nuclear dynamics of the Mre11 complex. 1111 2

Recent evidence from several investigators suggest that the human T-cell leukemia virus type 1 Tax oncoprotein represses the transcriptional activity of the tumor suppressor protein, p53. An examination of published findings reveals serious controversy as to the mechanism(s) utilized by Tax to inhibit p53 activity and whether the same mechanism is used by Tax in adherent and suspension cells. Here, we have investigated Tax-p53 interaction simultaneously in adherent epithelial (HeLa and Saos) and suspension T-lymphocyte (Jurkat) cells. Our results indicate that Tax activity through the CREB/CREB-binding protein (CBP), but not NF-kappaB, pathway is needed to repress the transcriptional activity of p53 in all tested cell lines. However, we did find that while CBP binding by Tax is necessary, it is not sufficient for inhibiting p53 function. Based on knockout cell studies, we correlated a strong genetic requirement for the ATM, but not protein kinase-dependent DNA, protein in conferring a Tax-p53-repressive phenotype.
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PMID:Genetic evidence of a role for ATM in functional interaction between human T-cell leukemia virus type 1 Tax and p53. 1111 8

Epidemiological studies have suggested that ataxia-telangiectasia (AT) heterozygotes have a predisposition to cancer, especially breast cancer in women. Now, haplotyping can identify heterozygotes for AT mutation (ATM) in AT families, allowing the risk of cancer associated with ATM heterozygosity status to be better assessed. We report a family study of AT patients, in which we estimated the risk of cancer according to ATM heterozygosity status. We analyzed demographic characteristics and occurrence of cancer in 1,423 relatives of AT patients. Haplotyping was performed in living relatives. The probability of being heterozygotes for ATM was calculated for deceased relatives. The risk of developing cancer was estimated in the cohort of relatives, and expected numbers of cancer cases were calculated from French age period-specific incidence rates. The number of cancers at all sites in the total population of relatives was not higher than expected. However, significant heterogeneity was found according to ATM heterozygosity status. This is mainly due to the increased risk of breast cancer previously observed in obligate heterozygotes. In obligate heterozygotes, relative risk (RR) was non-significantly increased for thyroid cancer, leukemia and liver cancer. Risks of ovarian, lung, pancreatic, kidney, stomach and colorectal cancers were non-significantly increased in the group with 0.5 probability of being heterozygotes. The RR was not significantly increased for any site of cancer, except for breast. Therefore, there is no evidence that specific screening of relatives of AT patients would be justified at particular sites other than the breast. However, the amplitude of the risk of breast cancer estimated in heterozygous women does not appear to justify a separate screening program from that already available to women with a first-degree relative affected by breast cancer.
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PMID:Cancer risk in heterozygotes for ataxia-telangiectasia. 1141 Aug 79

Ataxia telangiectasia (AT) is a rare multisystem, autosomal, recessive disease characterised by neuronal degeneration, genome instability, and an increased risk of cancer. Approximately 10% of AT homozygotes develop cancer, mostly of the lymphoid system. Lymphoid malignancies in patients with AT are of both B cell and T cell origin, and include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukaemia. The AT locus was mapped to the chromosomal region 11q22-23 using genetic linkage analysis in the late 1980s and the causative gene was identified by positional cloning several years later. The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. Most mutations in ATM result in truncation and destabilisation of the protein, but certain missense and splicing errors have been shown to produce a less severe phenotype. AT heterozygotes have a slightly increased risk of breast cancer. Atm deficient mice exhibit many of the symptoms found in patients with AT and have a high frequency of thymic lymphoma. The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atm deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy. Loss of heterozygosity at 11q22-23 (the location of the ATM gene) is a common event in lymphoid malignancy. Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL). In contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in these sporadic lymphoid malignancies were missense mutations. The presence of inactivating mutations, together with the deletion of the normal copy of the ATM gene in some patients with T-PLL, B-CLL, and MCL, establishes somatic inactivation of the ATM gene in the pathogenesis of lymphoid malignancies, and strongly suggests that ATM functions as a tumour suppressor. The presence of missense mutations in the germline of patients with B-CLL has been reported, suggesting that some patients with B-CLL may be constitutional AT heterozygotes. The putative hereditary predisposition of B-CLL, although intriguing, warrants further investigation.
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PMID:Ataxia telangiectasia gene mutations in leukaemia and lymphoma. 1142 21

Chronic myeloid leukaemia (CML) is characterised by an indolent, chronic phase (CP) preceding an acute transformation to blast crisis (BC). While the BCR-ABL fusion oncogene is strongly implicated in the CP, the molecular changes underlying BC are largely unknown. The ataxia telangiectasia gene, ATM, is a candidate gene for this transformation because the complex karyotypes associated with BC of CML suggest that DNA double-strand break repair is defective and because the ABL pathway involves the interaction between the Abl and the Atm proteins. We performed a mutational analysis for ATM in CML using genomic DNA from 14 CML cell lines and 59 CML patients in BC. No clearly deleterious nucleotide changes were observed. A new polymorphism C4138T was discovered which results in a non-conservative amino acid substitution (H1380Y). This variant lies in the Atm recognition motif for the Abl protein. While ATM is unlikely to contribute substantially to CML, further investigation of the H1380Y substitution should clarify whether it has any functional effect.
Leukemia 2001 Sep
PMID:Investigation on the role of the ATM gene in chronic myeloid leukaemia. 1151 6

Deletions of 13q14.3 are well known in several malignancies and are thought to be associated with tumour suppressor function. The RB-1 gene is a tumour suppressor gene, but other loci including D13S319 and D13S25 telomeric to this within 13q14.3 are deleted in B-cell chronic lymphocytic leukaemia (B-CLL), multiple myeloma and non-Hodgkin's lymphoma, with varying clinical significance. The fluorescence in situ hybridization screening of 22 patients with T-prolymphocytic leukaemia (T-PLL) for deletions of 13q14.3 revealed loss of D13S25 in 17 cases (mean 40% range 13-98%), with 11 patients having at least a 20% deletion. Mapping the deletions for the RB-1, D13S319,and D13S25 loci revealed D13S25 as the most frequently deleted marker. However, patients with only the D13S25 deletion had low percentages of cells with the deletion (12-13%), suggesting that loss of D13S25 on its own may not provide sufficient growth advantage. The use of the YAC 954c12, which maps immediately adjacent to D13S25, defined the telomeric border of the deletion in some of the cases. Inv(14)(q11q32) and t(14;14)(q11;q32) are characteristic of T-PLL, but are also observed in premalignant T-cell clones in patients with ataxia telangiectasia. Transition to overt leukaemia may result from loss of suppressor function. Thus, 13q14.3 deletions could contribute to the development of overt leukaemia in T-PLL, but the involvement of more than one gene in the region cannot be excluded.
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PMID:Deletions of D13S25, D13S319 and RB-1 mapping to 13q14.3 in T-cell prolymphocytic leukaemia. 1152 51

Chronic lymphocytic leukaemia is the commonest adult leukaemia, however the pathogenesis is largely unknown. Since the 1980s specific chromosomal abnormalities have been identified, of which the commonest are deletions of chromosomes 6q, 11q23, 13q14 and 17q13 and trisomy 12. The search for the responsible oncogenes at these sites has proved to be extremely frustrating. There are many oncogenes at 11q23 but the exact gene(s) responsible have yet to be identified. Germline abnormalities of the ATM gene occur in about 18% of patients compared to a normal population carriage of 0.5% but not all studies agree that ATM is the gene responsible. Unfortunately, despite the identification of various minimally deleted regions and the full sequencing of 13q14 no oncogenes have been identified. All original studies suggested the presence of a autosomally recessive tumour suppressor gene at this site but more recent studies suggest this may not be the case and the pathogenesis is more complex than first thought. Similarly, no genes have been identified at 6q or on chromosome 12. We know that the p53 tumour suppressor gene at 17p13 is an important prognostic indicator but it occurs in a minority of patients (about 15%), usually in patients with advanced disease, and therefore probably is not of aetiological importance.
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PMID:Molecular abnormalities in B-cell chronic lymphocytic leukaemia. 1155 53

We analyzed the role of 4 genes, TCL-1, MTCP-1, TML-1 and ATM, in the early pathogenesis of T cell leukemia, with particular interest in the characteristics of long-standing non-leukemic clonal proliferations in ataxia-telangiectasia (A-T) patients. Five patients were studied: 4 patients had A-T (2 of whom had non-leukemic clonal proliferations [ATCP]), 1 had B cell lymphoma and 1 had T-ALL; a fifth patient with T-PLL did not have A-T. We measured the levels of expression for TCL-1, MTCP-1 and TML-1. TCL-1, not expressed in unstimulated mature T cells, was upregulated in the peripheral blood leukocytes (PBL) of the 2 A-T patients with ATCP. It was also expressed in the malignant cells of the A-T patient with B cell lymphoma and the T-PLL cells of the patient without A-T. In the same cells, MTCP-1 type A was expressed equally in all 5 patients, as well as in the controls; MTCP-1 type B transcripts were not observed. TML-1, also not expressed in unstimulated T cells, was expressed in the PBL of one A-T patient with ATCP and in the leukemic cells of the non-A-T T-PLL patient. These expression patterns were compared to cellular immunophenotypes. The non-leukemic clonal T cell populations had the characteristics of immature T cells. We conclude that TCL-1 and TML-1 play a role in cell proliferation and survival but are not pivotal genes in the progression to malignancy, even when the ATM gene is mutated. Additional genetic alterations must occur to initiate tumorigenesis.
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PMID:TCL-1, MTCP-1 and TML-1 gene expression profile in non-leukemic clonal proliferations associated with ataxia-telangiectasia. 1185 46

The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions in mature T cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. In transgenic animals, the deregulated expression of TCL1 leads to mature T cell leukemia, demonstrating the role of TCL1 in the initiation of malignant transformation in T cell neoplasia. Expression of high levels of Tcl1 have also been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Here we describe the phenotype of transgenic mice, E mu-TCL1, established with TCL1 under the control of a V(H) promoter-Ig(H)-E mu enhancer to target TCL1 expression to immature and mature B cells. Flow cytometric analysis reveals a markedly expanded CD5(+) population in the peritoneal cavity of E mu-TCL1 mice starting at 2 mo of age that becomes evident in the spleen by 3-5 mo and in the bone marrow by 5-8 mo. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, suggesting a preneoplastic expansion of CD5(+) B cell clones, with the elder mice eventually developing a chronic lymphocytic leukemia (CLL)-like disorder resembling human B-CLL. Our findings provide an animal model for CLL, the most common human leukemia, and demonstrate that deregulation of the Tcl1 pathway plays a crucial role in CLL pathogenesis.
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PMID:Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. 1201 54


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