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)

Abnormal expression of the nuclear-associated enzyme DNA topoisomerase II (topoisomerase II) has been implicated in the in vitro phenotype of radiation hypersensitive ataxia-telangiectasia (A-T) cells and in modifying sensitivity of eukaryotic cells to topoisomerase II-inhibitor drugs [e.g., the DNA intercalator amsacrine (mAMSA)]. To study such relationships, various SV40- and Epstein-Barr Virus-transformed human cell lines derived from normal, A-T, or UV-sensitive xeroderma pigmentosum donors have been assayed for their sensitivity to mAMSA together with direct and indirect measurements of topoisomerase II expression. We report on the identification of an SV40-transformed A-T fibroblast cell line with abnormally high levels of topoisomerase II in nuclear protein extracts as determined by immunoblotting, measurement of kinetoplast DNA decatenation activity, and mAMSA-dependent DNA-protein cross-linking activity in a filter binding assay. Using a flow cytometric assay for the analysis of reactivity of nuclei with a polyclonal antitopoisomerase II antibody, overproduction was found to occur in all phases of the cell cycle. High levels of topoisomerase II were associated with hypersensitivity (5-10-fold) to mAMSA-induced cell cycle delay, cell kill, and DNA strand breakage (assayed under protein-denaturing conditions). Xeroderma pigmentosum (group A) cells demonstrated normal responses to mAMSA. The results provide evidence that cellular potential for the generation of topoisomerase II-dependent DNA damage is a major factor in governing the sensitivity to mAMSA. Furthermore, underexpression of topoisomerase II does not appear to be a primary factor in describing the in vitro A-T phenotype. The findings also relate to how changes in chromatin structure and function may either reflect or dictate the expression of topoisomerase II in human cells.
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PMID:Cellular consequences of overproduction of DNA topoisomerase II in an ataxia-telangiectasia cell line. 253 42

Exposure of human cells to gamma-radiation causes levels of the tumour-suppressor nuclear protein p53 to increase in temporal association with the decrease in replicative DNA synthesis. Cells from patients with the radiosensitive and cancer-prone disease ataxia telangiectasia (AT) exhibit radioresistant DNA synthesis and show a reduced or delayed gamma-radiation-induced increase in p53 protein levels. We have used Western immunoblotting with semiquantitative densitometry to examine the gamma-radiation-induced levels of p53 protein in 57 lymphoblastoid cell lines (LCLs) derived from patients with AT, carriers of the AT gene, breast cancer patients and normal donors. We confirm the previously reported reduced induction in AT homozygote LCLs (n = 8) compared with normal donor LCLs (n = 17, P = 0.01). We report that AT heterozygote LCLs (n = 5) also have a significantly reduced p53 induction when compared with LCLs from normal donors (n = 17, P = 0.02). The response of breast cancer patient cells was not significantly different from normal donor cells but 18% (5/27) had a p53 response in the AT heterozygote range (95% confidence interval) compared with only 6% (1/17) of the normal donor cells. We found no significant correlation between p53 induction and cellular radiosensitivity in LCLs from breast cancer patients. These methods may be useful in identifying individuals at greater risk of the DNA-damaging effects of ionising radiation.
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PMID:Induction of p53 protein by gamma radiation in lymphocyte lines from breast cancer and ataxia telangiectasia patients. 757 53

Angiotensin II (AII) binds to specific G protein-coupled receptors and is mitogenic in adrenal, liver epithelial, and vascular smooth muscle cells. Since the cyclin D1 gene encodes the regulatory subunit of the cyclin D1-dependent kinase (CD1K) required for phosphorylation of the retinoblastoma protein (pRB), an essential and rate-limiting step in G1 phase progression of the cell cycle, we examined the effect of AII on cyclin D1 expression and CD1K activity in the human adrenal cell line H295R. AII (10(-6) M) stimulated G1 phase progression within 12 h, with a maximal effect after 72 h. This action was antedated by the induction of cyclin D1 mRNA (3-fold), cyclin D1 nuclear protein abundance (4-fold), and CD1K activity (4-fold). AII induced cyclin D1 promoter activity 4-fold, via the AT1 receptor through an enhancer sequence at -954 base pairs. c-Fos and c-Jun bound the cyclin D1 -954 enhancer sequence, and the abundance of c-Fos within this complex was increased by AII treatment. AII induced extracellular signal-regulated kinase (ERK) activity 7-fold, and dominant-negative mutants of either p21(ras) or ERK reduced AII-stimulated cyclin D1 promoter activity. These findings suggest that AII may stimulate mitogenesis by increasing CD1K activity through a p21(ras)/ERK/activator protein 1 pathway.
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PMID:Angiotensin II activation of cyclin D1-dependent kinase activity. 879 25

The product of the dek oncogene is the 43-kDa DEK nuclear protein. DEK was first identified in a fusion with the CAN nucleoporin protein in a specific subtype of acute myelogenous leukemia. DEK has also been shown to be an autoantigen in patients with pauciarticular onset juvenile rheumatoid arthritis. Further, the last 65 amino acids of DEK can partially reverse the mutation-prone phenotype of cells from patients with ataxia-telangiectasia. However, in spite of these significant disease associations, the function of DEK has remained unclear. The HIV-2 peri-ets (pets) site is a TG-rich element found between the two Elf-1 binding sites in the HIV-2 enhancer. The pets element mediates transcriptional activation whether the enhancer is stimulated by phorbol 12-myristate 13-acetate (PMA) alone, phytohemagluttinin (PHA) alone, PMA plus PHA, soluble antibodies to the T cell receptor, immobilized antibodies to the T cell receptor, or by antigen. Previously, we purified and characterized the pets factor, demonstrating that it is a 43-kDa nuclear protein. We now describe the identification of DEK as this 43-kDa pets factor. Using a modified Southwestern screening procedure, we find that DEK can recognize the pets element. We demonstrate the ability of recombinant DEK to bind specifically to the pets site using the electrophoretic mobility shift assay (EMSA) and DNase I footprinting. "Supershift" EMSA further confirms that DEK is the dominant protein binding to the pets site in T cell extracts. Our findings show that DEK is a site-specific DNA binding protein that is likely involved in transcriptional regulation and signal transduction. This has implications for multiple pathogenic processes, including hematologic malignancies, arthritis, ataxia-telangiectasia, and AIDS caused by HIV-2.
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PMID:DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer. 905 Aug 61

Ataxia-telangiectasia is a rare recessive disorder which, among other clinical signs, is characterized by an extreme sensitivity to ionising radiation. Cells isolated from AT patients show radioresistant DNA synthesis and this has lead to the hypothesis that the product of the genetic determinant of AT may play a role in the detection, signalling or repair of double stranded DNA breaks. The gene to AT, called ATM has been recently cloned and characterized. It codes for a large RNA transcript of 13,000 bp of which a 3,500 aa protein is translated. The gene itself covers 150 kb, spread over 64 exons. The amino acid sequence has revealed the existence, at the carboxyterminal end of the protein, of a domain presenting homology to PI-3 kinase. This characteristic has allowed the description of a new family of nuclear protein, in yeast, drosophila an human, functionally involved in DNA damage signalling. It is interesting to note that a vast majority of mutations described in AT patients lead to the truncation of the protein and consequently to the elimination of the PI-3K domain, thus suggesting an important role in the normal function of the protein. An important question linked to AT mutation concerns the cancer risk associated to heterozygous mutations. It is well established that AT patients, homozygous for the mutation, present a 100-200 fold increased risk of cancer. Epidemiological studies have described a 3-5 fold increase risk of cancer (particular breast cancer in women) associated to the heterozygous mutation. Knowing that the incidence of the heterozygotes can be estimated to range 0.5 to 1% in the general population this question is of great importance in terms of public health.
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PMID:[Ataxia-telangiectasia and cancer: an open question]. 933 5

DNA-dependent protein kinase (DNA-PK) is a nuclear protein serine/threonine kinase that is activated by DNA double strand breaks (DSBs). It is a component of the DNA DSB repair apparatus, and cells deficient in DNA-PK are hypersensitive to ionising radiation and radio-mimetic drugs. In addition, DNA-PK is required to generate the antigen binding sites of T-cell receptor and immunoglobulin molecules, and the phenotype of the severe combined immunodeficient (scid) mouse is due to a DNA-PK deficiency. Recent data suggest that DNA-PK may also have roles in controlling transcription, apoptosis, and the length of telomeric chromosomal ends. Finally, DNA-PK is related to other proteins involved in DNA damage detection, including the protein defective in the human neurodegenerative and cancer predisposition syndrome ataxia-telangiectasia. Studies on DNA-PK should provide a better understanding of degenerative disease and cancer, and may lead to improved therapies for these conditions.
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PMID:DNA-dependent protein kinase. 937 73

Severe combined immunodeficiency (SCID) mice are defective in their ability to rearrange their variable (V), diversity (D) and joining (J) genetic elements to generate functional immunoglobulin (Ig) and T-cell receptor (TCR) molecules; as a result, they lack mature B and T cells. These mice are highly sensitive to ionizing radiation, suggesting that the product of the scid gene plays a critical role in both V(D)J recombination and DNA double-strand break repair. Recent studies suggest that the SCID defect lies in the gene encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PK; refs 6-8), a nuclear protein made up of the Ku 70 and Ku 86 subunits as well as the large catalytic subunit, DNA-PKcs. Other reports have implied that the SCID phenotype correlates with nonsense mutations at the extreme 3' end of Prkdc, the DNA-PKcs gene. The identity of the gene remains in doubt, however, because the consequences of genetic inactivation of Prkdc have not been determined. This study shows that complete inactivation of Prkdc in a novel insertional mouse mutant recapitulates the SCID phenotype and that Prkdc and scid are alleic. Significantly, DNA-PKcs null mice demonstrate complete penetrance of thymic lymphoblastic lymphomas, strongly suggesting that Prkdc functions in mice as a T-cell tumour suppressor and, by virtue of its association with DNA repair and recombination, belongs to the 'caretaker' class of tumour-suppressor genes that includes ATM, BRCA1 and BRCA2 (ref. 15).
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PMID:DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. 939 56

The gene mutated in the human genetic disorder ataxia-telangiectasia, ATM, is implicated in the response to radiation-induced DNA damage and to a more widespread signalling defect. The ATM protein is predominantly a nuclear protein where it interacts with p53 and c-Abl as part of a radiation signal transduction pathway(s). We describe here the cloning of full-length ATM cDNA in a baculovirus vector to produce recombinant protein. Expression of ATM, as a soluble protein, was observed by 36 h post-infection using immunoblotting with anti-ATM antibody. The presence of a hexahistidine tag on ATM was used as the basis for purification of the protein by affinity chromatography. The protein yield was only 20 ng/100 ml of infected cells, presumably because of the size of the protein and adverse effects on cell growth when overexpressed. ATM was found to have autophosphorylation activity in immunoprecipitates with antibodies directed against the hexahistidine tag sequence. These results demonstrate that ATM can be expressed inefficiently in baculovirus infected insect cells and the data suggest that it phosphorylates itself.
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PMID:Cloning and expression of the ataxia-telangiectasia gene in baculovirus. 953 98

Ataxia telangiectasia-mutated gene (ATM) is a 350-kDa protein whose function is defective in the autosomal recessive disorder ataxia telangiectasia (AT). Affinity-purified polyclonal antibodies were used to characterize ATM. Steady-state levels of ATM protein varied from undetectable in most AT cell lines to highly expressed in HeLa, U2OS, and normal human fibroblasts. Subcellular fractionation showed that ATM is predominantly a nuclear protein associated with the chromatin and nuclear matrix. ATM protein levels remained constant throughout the cell cycle and did not change in response to serum stimulation. Ionizing radiation had no significant effect on either the expression or distribution of ATM. ATM immunoprecipitates from HeLa cells and the human DNA-dependent protein kinase null cell line MO59J, but not from AT cells, phosphorylated the 34-kDa subunit of replication protein A (RPA) complex in a single-stranded and linear double-stranded DNA-dependent manner. Phosphorylation of p34 RPA occurred on threonine and serine residues. Phosphopeptide analysis demonstrates that the ATM-associated protein kinase phosphorylates p34 RPA on similar residues observed in vivo. The DNA-dependent protein kinase activity observed for ATM immunocomplexes, along with the association of ATM with chromatin, suggests that DNA damage can induce ATM or a stably associated protein kinase to phosphorylate proteins in the DNA damage response pathway.
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PMID:Characterization of ATM expression, localization, and associated DNA-dependent protein kinase activity. 972 99

The c-Jun amino-terminal kinases (JNKs) participate in intracellular signaling in response to cytokines and cellular stresses. JNKs are activated by phosphorylation on two critical residues, the threonine 183 and tyrosine 185, within the TPY motif. The activated JNKs, in turn, phosphorylate the nuclear protein c-Jun, a major component of the transcription factor AP1. In vitro studies have revealed a defect in ionizing radiation-induced activation of the JNK signaling pathway in lymphoblastoid cells from individuals with ataxia telangiectasia (AT). However, the biochemical basis for this signaling defect is not clear. Here, we show that ionizing radiation induces the phosphorylation of endogenous c-Jun in normal fibroblasts but not in AT fibroblasts. The p46 isoforms of dually phosphorylated JNKs were detected in the nuclei of both normal and AT fibroblasts following exposure to ionizing radiation or sham radiation. However, c-Jun kinase activity was detected in normal cells but not in AT cells. Furthermore, an exogenous purified active JNK protein was able to phosphorylate endogenous c-Jun in nuclear extracts only of normal cells and only after the cells were irradiated. Electrophoretic mobility shift assays also showed that the ionizing radiation-induced increase in the DNA binding activity of AP1 observed in normal cells was absent or markedly reduced in AT cell lines. These data suggest that the defect in ionizing radiation-induced signaling through c-Jun in AT cells is the result of impaired function of an unknown nuclear protein or proteins that negatively regulate both JNK and c-Jun.
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PMID:Impaired ionizing radiation-induced activation of a nuclear signal essential for phosphorylation of c-Jun by dually phosphorylated c-Jun amino-terminal kinases in ataxia telangiectasia fibroblasts. 983 38


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