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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of ionizing radiation on the expression of two DNA-damage-inducible genes, designated gadd45 and gadd153, was examined in cultured human cells. These genes have previously been shown to be strongly and coordinately induced by UV radiation and alkylating agents in human and hamster cells. We found that the gadd45 but not the gadd153 gene is strongly induced by X rays in human cells. The level of gadd45 mRNA increased rapidly after X rays at doses as low as 2 Gy. After 20 Gy of X rays, gadd45 induction, as measured by increased amounts of mRNA, was similar to that produced by the most effective dose of the alkylating agent methyl methanesulfonate. No induction was seen after treatment of either human or hamster cells with 12-O-tetradecanoylphorbol-13-acetate, a known activator of protein kinase C (PKC). Therefore, gadd45 represents the only known mammalian X-ray-responsive gene whose induction is not mediated by PKC. However, induction was blocked by the protein kinase inhibitor H7, indicating that induction is mediated by some other kinase(s). Sequence analysis of human and hamster cDNA clones demonstrated that this gene has been highly conserved and encodes a novel 165-amino-acid polypeptide which is 96% identical in the two species. This gene was localized to the short arm of human chromosome 1 between p12 and p34. When induction in lymphoblast lines from four normal individuals was compared with that in lines from four patients with ataxia telangiectasia, induction by X rays of gadd45 mRNA was less in the cell lines from this cancer-prone radiosensitive disorder. Our results provide evidence for the existence of an X-ray stress response in human cells which is independent of PKC and which is abnormal in taxia telangiectasia.
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PMID:Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C. 199 Feb 62

Twenty-one patients with T-prolymphocytic leukemia (T-PLL) were studied by FISH to characterize abnormalities of chromosomes 8, 11, 14, and X. A higher percentage of abnormalities of these chromosomes was detected by FISH than by cytogenetics. Seventy-one percent had inv(14) (q11q32)/t(14;14)(q11;q32). Four patients had abnormalities involving Xq28 (MTCP-1 locus) resulting from t(X;14)(q28;q11) or t(X;7)(q28;q35). These abnormalities have also been described in persistent expanding pre-malignant T-cell clones in patients with ataxia telangiectasia (AT). We have previously reported that in T-PLL and AT developing T-cell leukemia, the above abnormalities occur with additional abnormalities, mainly trisomy for 8q resulting predominantly from an i(8)(q10) and an increased expression of MYC. In this series, 81% of cases had chromosome 8 abnormalities including i(8)(q10)[43%]/t(8;8)(p12;q11)[14%], + 8[14%], and 8p + [14%]. The use of probes for MYC (8q24) and chromosome 8 centromere on metaphase chromosomes revealed that cases with i(8)(q10) were dicentric and t(8;8) monocentric. These abnormalities are not only associated with increase in dosage of 8q and the MYC gene, but also involved 8p. 8p is known to have several suppressor genes associated with solid tumors. Our findings suggest that the possible loss of a tumor suppressor gene plus the increased dosage of the q arm and/or the high expression of TCL-1/MTCP-1, which results from inv(14)/t(14;14), allows the malignant phenotype to emerge.
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PMID:Abnormalities of chromosomes 8, 11, 14, and X in T-prolymphocytic leukemia studied by fluorescence in situ hybridization. 961 8

Mammalian DNA polymerase (Pol) delta is essential for DNA replication. It consists of four subunits, p125, p50, p68, and p12. We report the discovery that the p12 subunit is rapidly degraded in cultured human cells by DNA damage or replication stress brought about by treatments with UV, methyl methanesulfonate, hydroxyurea, and aphidicolin. The degradation of p12 is due to an accelerated rate of proteolysis that is inhibited by the proteasome inhibitors, MG132 and lactacystin. UV treatment converts Pol delta in vivo to the three-subunit form lacking p12. This was demonstrated by its isolation using immunoaffinity chromatography. The three-subunit enzyme retains activity on poly(dA)/oligo(dT) templates but is impaired in its ability to extend singly primed M13 templates, clearly indicating that its in vivo functions are likely to be compromised. This transformation of Pol delta by modification of its quaternary structure is reversible in vitro by the addition of the p12 subunit and could represent a novel in vivo mechanism for the modulation of Pol delta function. UV and hydroxyurea-triggered p12 degradation is blocked in ATR(-/-) cells but not in ATM(-/-) cells, thereby demonstrating that p12 degradation is regulated by ATR, the apical kinase that regulates the damage response in S-phase. These findings reveal a novel addition to the cellular repertoire of DNA damage responses that also impacts our understanding of the role of Pol delta in both DNA replication and DNA repair.
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PMID:A novel DNA damage response: rapid degradation of the p12 subunit of dna polymerase delta. 1731 65

Lymphoplasmacytic lymphomas and marginal zone lymphomas of nodal, extra-nodal and splenic types account for 10% of non-Hodgkin lymphomas. They are similar at the cell differentiation level, sometimes making difficult to distinguish them from other indolent non-Hodgkin lymphomas. To better characterize their genetic basis, we performed array-based comparative genomic hybridization in 101 marginal zone lymphomas (46 MALT, 35 splenic and 20 nodal marginal zone lymphomas) and 13 lymphoplasmacytic lymphomas. Overall, 90% exhibited copy-number abnormalities. Lymphoplasmacytic lymphomas demonstrated the most complex karyotype (median=7 copy-number abnormalities), followed by MALT (4), nodal (3.5) and splenic marginal zone lymphomas (3). A comparative analysis exposed a group of copy-number abnormalities shared by several or all the entities with few disease-specific abnormalities. Gain of chromosomes 3, 12 and 18 and loss of 6q23-q24 (TNFAIP3) were identified in all entities. Losses of 13q14.3 (MIRN15A-MIRN16-1) and 17p13.3-p12 (TP53) were found in lymphoplasmacytic and splenic marginal zone lymphomas; loss of 11q21-q22 (ATM) was found in nodal, splenic marginal zone and lymphoplasmacytic lymphomas and loss of 7q32.1-q33 was found in MALT, splenic and lymphoplasmacytic lymphomas. Abnormalities affecting the nuclear factor kappa B pathway were observed in 70% of MALT and lymphoplasmacytic lymphomas and 30% of splenic and nodal marginal zone lymphomas, suggesting distinct roles of this pathway in the pathogenesis/progression of these subtypes. Elucidation of the genetic alterations contributing to the pathogenesis of these lymphomas may guide to design-specific therapeutic approaches.
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PMID:Genomic analysis of marginal zone and lymphoplasmacytic lymphomas identified common and disease-specific abnormalities. 2230 99

Oral squamous cell carcinoma (OSCC) is a common cancer in Taiwan and worldwide. To provide some clues for clinical management of OSCC, 72 advanced-stage OSCCs were analyzed using two microarray platforms (26 cases with Affymetrix 500 K and 46 cases with Affymetrix SNP 6.0). Genomic identification of significant targets in cancer analyses were used to identify significant copy number alterations (CNAs) using a q-value cutoff of 0.25. Among the several significant regions, 12 CNAs were common between these two platforms. Two gain regions contained the well-known oncogenes EGFR (7p11.2) and CCND1 (11q13.3) and several known cancer suppressor genes, such as FHIT (3p14.2-p12.1), FAT1 (4q35.1), CDKN2A (9p21.3), and ATM (11q22.3-q24.3), reside within the 10 deletion regions. Copy number gains of EGFR and CCND1 were further confirmed by fluorescence in situ hybridization and TaqMan CN assay, respectively, in 257 OSCC cases. Our results indicate that EGFR and CCND1 CNAs are significantly associated with clinical stage, tumor differentiation, and lymph node metastasis. Furthermore, EGFR and CCND1 CNAs have an additive effect on OSCC tumor progression. Thus, current genome-wide CNA analysis provides clues for future characterization of important oncogenes and tumor suppressor genes associated with the behaviors of the disease.
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PMID:Amplification of the EGFR and CCND1 Are Coordinated and Play Important Roles in the Progression of Oral Squamous Cell Carcinomas. 3115 51

The rate of genetic diagnosis of French patients with familial pancreatic ductal adenocarcinoma (PDAC) is not known. We report germline genetic testing data from 133 index cases meeting criteria for familial pancreatic cancer (FPC) as well as 87 'FPC-like' index cases who did not fulfilled strict FPC definition but were evocative for a PDAC predisposition. The overall rate of genetic diagnosis (in BRCA1, BRCA2, CDKN2A, and ATM genes) was 8.3% in FPC patients and 4.6% in FPC-like patients, consistent with the literature in other populations. Genetic variants were also identified in FANCA and BAP1 genes, as well as in the CDKN2A p12 transcript. This pancreas-specific transcript is a known key player in driving pancreatic oncogenesis. This might be the first described case of a PDAC genetic predisposition due to a variant in this specific transcript.
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PMID:Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort. 3143 1