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)

Cells derived from a patient with severe chromosomal breakage, immunodeficiency, and growth retardation were found to resemble those from individuals with ataxia telangiectasia (A-T) in terms of their sensitivity to cell killing and the induction of cytogenetic abnormalities by X-rays. Their response to other DNA-damaging agents, including 254-nm UV light, mitomycin C, MNNG, and bleomycin was also A-T-like. In contrast to classical A-T, however, X-irradiated cells exhibited a G1 block after release from density inhibition of growth that was not significantly different from that of normal controls.
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PMID:Hypersensitivity of cells from a new chromosomal-breakage syndrome to DNA-damaging agents. 378 61

Methylnitronitrosoguanidine (MNNG) is reported to inhibit DNA synthesis in intact human cells, in the cells from patients with ataxia telangiectasia (AT) or the cells from two rodent species. DNA synthesis in different cell lines exhibits varying sensitivity to MNNG inhibitory effect. 4-5-fold higher concentrations of MNNG are required for 50% inhibition of DNA synthesis in AT cells or in field vole cells as compared with the concentration required for human cells or Chinese hamster. The different compactness of two chromatin fractions might possibly result in lower sensitivity of DNA synthesis in heterochromatin to MNNG-induced inhibition as compared with the sensitivity of euchromatin. The genetic expression of AT defect on the cellular level is supposed to be connected with changes in supramolecular packaging of chromatin in interphase nuclei.
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PMID:[The effect of methylnitronitrosoguanidine on DNA synthesis in human and animal cells. Inhibition of DNA synthesis in asynchronous and synchronous cultured cells]. 391 33

We have provided experimental evidence in favour of the hypothesis that carcinogenesis is triggered by at least two chromosomal events, which must occur in a single diploid somatic cell in a specific time sequence: (i) specific recessive mutational or epigenetic chromosomal change(s) resulting in a heterozygous (m/+), latently premalignant state (initiation); this must be followed by (ii) a chromosomal rearrangement involving the affected locus, and leading to homozygosity (m/m) or hemizygosity (m/o), and subsequent expression of the recessive malignant character (promotion). The complete carcinogen, MNNG, induced mutations (6-thioguanine-resistance), chromosomal rearrangements and SCEs in V79 Chinese hamster cells. TPA, a potent tumour promoter, induced only SCEs and specific chromosomal effects. Antipain, a protease inhibitor and a known inhibitor of both carcinogenesis and tumour promotion, inhibited only the MMNG-induced chromosomal rearrangements (but not mutagenesis and SCEs) and the TPA-induced chromosomal events. These results suggest that (1) both TPA-induced and MNNG-induced chromosomal rearrangements are caused by the activation or induction of mitotic recombination and hence appear to be preventable; (2) chromosomal rearrangement is a rate-limiting step in carcinogenesis; and (3) if mutagenesis is involved in carcinogenesis, it is probably not sufficient. The existence of the human cancer-prone syndromes, Bloom's, Fanconi's anaemia and ataxia telangiectasia, which involve spontaneous chromosomal rearrangements analogous to those induced by carcinogens in normal cells, strongly supports our hypothesis that carcinogenesis involves two chromosomal events. We discuss the implications of this work to carcinogenicity testing and cancer prevention strategies.
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PMID:Chromosomal events in carcinogenic initiation and promotion: implications for carcinogenicity testing and cancer prevention strategies. 700 84

The basic leucine zipper transcription factor, CCAAT/enhancer binding protein alpha (C/EBPalpha), is abundantly expressed in keratinocytes of the skin; however, its function in skin is poorly characterized. UVB radiation is responsible for the majority of human skin cancers. In response to UVB-induced DNA damage, keratinocytes activate cell cycle checkpoints that arrest cell cycle progression and prevent replication of damaged DNA, allowing time for DNA repair. We report here that UVB radiation is a potent inducer of C/EBPalpha in human and mouse keratinocytes, as well as in mouse skin in vivo. UVB irradiation of keratinocytes resulted in the transcriptional up-regulation of C/EBPalpha mRNA, producing a >70-fold increase in C/EBPalpha protein levels. N-Methyl-N'-nitro-N-nitrosoguanidine, etoposide, and bleomycin also induced C/EBPalpha. UVB-induced C/EBPalpha was accompanied by an increase in p53 protein and caffeine, an inhibitor of ataxia-telangiectasia-mutated kinase, and ataxia-telangiectasia-mutated and Rad3-related kinase inhibited UVB-induced increases in both C/EBPalpha and p53. UVB irradiation of p53-null or mutant p53-containing keratinocytes failed to induce C/EBPalpha. UVB irradiation of C/EBPalpha knockdown keratinocytes displayed a greatly diminished DNA damage G(1) checkpoint, and this was associated with increased sensitivity to UVB-induced apoptosis. Our results uncover a novel role for C/EBPalpha as a p53-regulated DNA damage-inducible gene that has a critical function in the DNA damage G(1) checkpoint response in keratinocytes.
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PMID:C/EBPalpha is a DNA damage-inducible p53-regulated mediator of the G1 checkpoint in keratinocytes. 1557 70

The alkylating agent MNNG is an environmental carcinogen that causes DNA lesions leading to cell death. We previously demonstrated that MNNG induced the transcriptional activity of the plasminogen activator inhibitor-1 (PAI-1) gene in a p53-dependent manner. However, the mechanism(s) linking external MNNG stimulation and PAI-1 gene induction remained to be elucidated. Here, we show that ATM and ATR kinases, but not DNA-PK, which participate in DNA damage-activated checkpoints, regulate the phosphorylation of p53 at serine 15 in response to MNNG cell treatment. Using ATM-deficient cells, ATM was shown to be required for early phosphorylation of serine 15 in response to MNNG, whereas catalytically inactive ATR selectively interfered with late phase serine 15 phosphorylation. In contrast, DNA-PK-deficient cells showed no change in the MNNG-induced serine 15 phosphorylation pattern. In agreement with this, sequential activation of ATM and ATR kinases was also required for adequate induction of the endogenous PAI-1 gene by MNNG. Finally, we showed that cells derived from PAI-1-deficient mice were more resistant to MNNG-induced cell death than normal cells, suggesting that p53-dependent PAI-1 expression partially mediated this effect. Since PAI-1 is involved in the control of tumor invasiveness, our finding that MNNG induces PAI-1 gene expression via ATM/ATR-mediated phosphorylation of p53 sheds new insight on the role of these DNA damage-induced cell cycle checkpoint kinases.
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PMID:The alkylating carcinogen N-methyl-N'-nitro-N-nitrosoguanidine activates the plasminogen activator inhibitor-1 gene through sequential phosphorylation of p53 by ATM and ATR kinases. 1573 14

We recently discovered mutation signatures reminiscent of BRCA deficiency in the vast majority of a set of primary osteosarcomas (OS). In the current study, we therefore investigated the sensitivity of a panel of OS cell lines to the poly(ADP)-ribose polymerase (PARP) inhibitor talazoparib alone and in combination with several chemotherapeutic drugs (i.e. temozolomide (TMZ), SN-38, doxorubicin, cisplatin, methotrexate (MTX), etoposide/carboplatin). Here, we identified an association between homologous recombination (HR) repair deficiency and the response of OS cell lines to talazoparib. All OS cell lines with molecular features characteristic of BRCA1/2 mutant tumors (so-called "BRCAness"), such as disruptive gains in PTEN or FANCD2 and/or losses of ATM, BAP1, BARD1 or CHEK2, were susceptible to talazoparib-induced reduction of cell viability (i.e. MG63, ZK-58,, SaOS-2 and MNNG-HOS). Consistent with their high sensitivity to talazoparib, MG63 and ZK-58 cells scored positive in a DNA-based measure of genomic instability (i.e. homologous recombination deficiency (HRD)-loss of heterozygosity (LOH) score). In contrast, U2OS cells that carry a heterozygous BRCA2 mutation and therefore most likely have one intact BRCA2 allele left proved to be resistant to talazoparib. Furthermore, we identified TMZ as the most potent chemotherapeutic drug together with talazoparib to synergistically reduce cell viability, as confirmed by calculation of combination index (CI) values, and to suppress long-term clonogenic survival. Mechanistically, talazoparib and TMZ cooperated to induce apoptotic cell death, as demonstrated by activation of BAX and BAK, loss of mitochondrial membrane potential (MMP), caspase activation, DNA fragmentation and caspase-dependent cell death. Genetic silencing of BAX and BAK or pharmacological inhibition of caspases by zVAD.fmk significantly rescued OS cells from talazoparib/TMZ-induced apoptosis. These findings have important implications for the development of novel treatment strategies using PARP inhibitors alone or together with chemotherapy in a subset of OS with features of BRCAness.
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PMID:Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics. 2744 64