UMLS:C0004135 - FACTA Search

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

We have shown previously that angiotensin-II (A-II) controls proto-oncogene (c-fos, jun-B and c-jun) mRNA accumulation in bovine adrenal fasciculata cells (BAC). Since BAC contain both subtypes (AT-1 and AT-2) of the A-II receptor, we have investigated which subtype was involved in the effect of A-II on proto-oncogene mRNA by using a selective antagonist for AT-1 (DUP 753) and for AT-2 (CGP 42112A). DUP 753, but not CGP 42112A, inhibited the stimulatory effect of A-II on proto-oncogene mRNA, with ID50s of 4 x 10(-7) M, 7 x 10(-7) M and 2 x 10(-6) M for c-fos, jun-B and c-jun, respectively. Neither of the two antagonists by themselves had a direct effect on proto-oncogene mRNA. As the A-II AT-1 receptors are coupled to the phospholipase C system in BAC, we have investigated whether the A-II effects on the proto-oncogenes were mediated by protein kinase C (PKC) or by Ca2+ calmodulin. First, activation of PKC by the phorbol ester, PMA, increased the level of three proto-oncogene mRNAs, whereas calcium ionophore had no effect. Second, staurosporine, a specific inhibitor of PKC, reduced the stimulatory action of A-II on proto-oncogene mRNA by 80-90%, whereas trifluoroperazine, an inhibitor of calmodulin, had no significant effect. These results demonstrate that the effects of A-II on proto-oncogene mRNA are mediated by AT1 receptor subtypes, mainly through activation of the PKC pathway.
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PMID:Angiotensin-II-induced expression of proto-oncogene (c-fos, jun-B and c-jun) mRNA in bovine adrenocortical fasciculata cells (BAC) is mediated by AT-1 receptors. 142 67

In isolated rat hepatocytes PMA, angiotensin II and to a lesser extent other hormones induce an early genetic response (increased expression of c-fos, c-mos, c-myc and beta-actin) without altering the expression of the glyceraldehyde 3-phosphate dehydrogenase gene. PMA, PDB and O-met-PMA, but not alpha-phorbol, stimulated c-fos expression. The effect of angiotensin II was inhibited by the AT1 antagonist, Losartan (DuP 753) (Ki approx. 25 nM), but not by the AT2 antagonist PD123177. Angiotensin II was much more effective than vasopressin or epinephrine in inducing proto-oncogene expression which suggests that angiotensin II receptors may exert actions in addition to those shared with the receptors for the other calcium-mobilizing hormones. The effect of PMA and angiotensin II on c-fos expression took place rapidly, with half times of 7 and 12 min, respectively. Actinomycin D markedly diminished basal c-fos expression whereas cycloheximide had the opposite effect. Actinomycin D diminished the effect of PMA and angiotensin II but it did not block them. PMA and the calcium-mobilizing hormones increased c-fos expression above the level observed with cycloheximide alone. These data suggest that PMA and the calcium-mobilizing hormones increased both transcription of the c-fos gene and stabilization of the proto-oncogene mRNA.
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PMID:Angiotensin II and active phorbol esters induce proto-oncogene expression in isolated rat hepatocytes. 152 Jul 5

Lymphomas occurred in 3 of 16 Japanese patients with ataxia telangiectasia (AT) and Wiskott-Aldrich syndrome (WAS). The patients had a persistently reactivated Epstein-Barr virus (EBV) infection with a remarkable decrease in virus-specific cellular immunity. In these patients, the B lymphocytes were more sensitive to EBV-induced events and to cellular proto-oncogene activation than seen in the healthy counterparts. This immunologic and genetic background was considered to explain the massive lymphoproliferation in these primary immunodeficiency disorders.
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PMID:Epstein-Barr virus infection and oncogenesis in primary immunodeficiency. 303 Mar 41

Using cultured bovine adrenal fasciculata cells (BAC), we investigated the effects of two hormones, corticotropin (ACTH) and angiotensin II (Ang-II) and two growth factors, insulin-like growth factors I (IGF-I) and transforming growth factor beta 1 (TGF beta 1), on the mRNA levels of nuclear proto-oncogenes of the Fos and Jun families and on the mRNA levels of genes expressed in BAC coding for ACTH and AT1 receptors, cytochrome P450scc and P450 17 alpha and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). ACTH and IGF-1 increased c-fos and jun-B mRNA levels early with later increases in the levels of mRNA for the ACTH receptor and the three steroidogenic enzymes, and enhanced steroidogenic responses to both ACTH and Ang-II. In contrast, Ang-II increased mRNA coding for the three proto-oncogenes (cfos, c-jun, and jun-B), decreased those for P450 17 alpha and 3 beta-HSD, and caused marked homologous and heterologous steroidogenic desensitization. TGF beta 1 increased only jun-B mRNA and markedly reduced BAC-differentiated functions and steroidogenic responsiveness to both ACTH and Ang-II. The long-term effects of ACTH on human adrenal fasciculata cells were comparable with those observed in BAC, whereas the long term effects of Ang-II and TGF beta 1 were different from those observed in BAC. Whether these species-specific differences are related to a different effect of these factors on proto-oncogene expression is not yet known.
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PMID:Regulation of primary response and specific genes in adrenal cells by peptide hormones and growth factors. 873 96

Chromosome 11q23 is frequently a site of chromosomal translocation in both acute leukemias and chronic lymphoproliferative disorders. In the former, an 8 kb region within the MLL gene is consistently involved, whereas in the latter breakpoints appear to be heterogeneous. In a B cell acute leukemia cell line with t(14;18)(q32.3;q21.3) we have previously demonstrated a reciprocal translocation between the LAZ3/BCL6 gene at 3q27 and the B cell specific transcriptional coactivator gene BOB-1 at 11q23.1, implicating BOB-1 as a potential proto-oncogene. To confirm the chromosomal localization of BOB-1 we have mapped it by FISH to 11q23.1. It lay immediately telomeric of the ATM gene. We have also investigated the frequency of BOB-1 rearrangements in a panel of 32 cell lines and 71 patient samples. In one case of T cell prolymphocytic leukemia-a disease where 11q23 abnormalities are observed-a chromosomal rearrangement was identified 3.3-0.9 kb centromeric of the 3' end of the gene. Thus, there is a heterogeneity of breakpoints associated with BOB-1 while the frequency of the gene's involvement in lymphoproliferative diseases is low.
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PMID:Heterogeneity of breakpoints at the transcriptional co-activator gene, BOB-1, in lymphoproliferative disease. 875 68

Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with pleiotropic phenotypes, including neuronal degeneration, immune dysfunction, premature ageing and increased cancer risk. The gene mutated in AT, ATM, encodes a putative lipid or protein kinase. Most of the human AT patient phenotypes are recapitulated in Atm-deficient mice. Cells derived from Atm-/- mice, like those from AT patients, exhibit abnormal response to ionizing radiation. One of the known responses to ionizing radiation is the activation of a nuclear tyrosine kinase encoded by the c-abl proto-oncogene. Ionizing radiation does not activate c-Abl in cells from AT patients or in thymocytes or fibroblasts from the Atm-deficient mice. Ectopic expression of a functional ATM kinase domain corrects this defect, as it phosphorylates the c-Abl tyrosine kinase in vitro at Ser 465, leading to the activation of c-Abl. A mutant c-Abl with Ser 465 changed to Ala 465 is not activated by ionizing radiation or ATM kinase in vivo. These findings identify the c-Abl tyrosine kinase as a downstream target of phosphorylation and activation by the ATM kinase in the cellular response to ionizing radiation.
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PMID:Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. 916 2

Radiosensitivity is a major hallmark of the human genetic disorder ataxia telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vivo after exposure of patients to therapeutic doses of radiation and in cells in culture. Clearly an understanding of the nature of the molecular defect in ataxia telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas, the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia telangiectasia (A-T)? As outlined above, since radiosensitivity is a universal characteristic of A-T, understanding the mechanism of action of ATM will provide additional information on radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM-controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense cDNA constructs into tumours to achieve the same end-point.
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PMID:Radiosensitivity and oxidative signalling in ataxia telangiectasia: an update. 968 57

To study the effects of specific angiotension II (Ang II) receptor, type-1 (AT1) antagonist (Losartan) and type-2 (AT2) antagonist (PD123319), on Ang II-induced proto-oncogene expression and synthesis of RNA and protein in neonatal rat cardiac myocytes, we used respectively [3H]-uridine and [3H]-leucine incorporation to measure the rate of RNA and protein synthesis, and analyzed the c-myc mRNA level by Northern blot. We found that an acceleration in the rate of RNA and protein synthesis was observed when exposed to 2.5 x 10(-6) mol.L-1 [Sar1] Ang II for 24 h (P < 0.01). Losartan inhibited the action in a dose-dependent manner. The level of c-myc mRNA was up-regulated to 340% of control by 2.5 x 10(-6) mol.L-1 Ang II, and Losartan (10(-5) mol.L-1) suppressed the increase of c-myc mRNA stimulated by Ang II. PD123319 showed similar inhibition on Ang II-induced RNA and protein synthesis, but did not inhibit c-myc expression. Thus, Ang II-stimulated expression of c-myc is mainly mediated by AT1 receptors, and contributes to cardiac myocyte hypertrophy while AT2 receptors are involved in mediation of cellular growth without altering of c-myc expression.
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PMID:Effects of losartan and PD123319 on antigensin II-induced proto-oncogene expression and protein synthesis in cultured neonatal rat cardiac myocytes. 986 75

In C9 (Clone 9) liver cells, angiotensin 11 increased the intracellular Ca2+ content, inositol phosphate production and c-fos mRNA expression. Other angiotensins were also active with the order of potency being angiotensin II = angiotensin III >> angiotensin I > angiotensin IV. Losartan, but not PD 123177 (1-(4-amino-3-methyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imida zo [4,5c]pyridine-6-carboxylic acid), blocked the effects of angiotensin II. Pertussis toxin did not alter these actions of angiotensin II. These data indicate that the effects were mediated through angiotensin AT1 receptors involving pertussis toxin-insensitive G-proteins. Phorbol myristate acetate was also able to increase c-fos mRNA expression. The action of angiotensin II was consistently greater than that of the active phorbol ester. Staurosporine but not genistein inhibited this effect of angiotensin II. Angiotensin II- and phorbol myristate acetate-induced proto-oncogene mRNA expression was attenuated in cells incubated overnight with the active phorbol ester, which suggests a major role of protein kinase C.
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PMID:Angiotensin AT1 receptors in Clone 9 rat liver cells: Ca2+ signaling and c-fos expression. 987 76

A Task Group of the ICRP Committee 1 (Radiation Effects) has reviewed relevant data with the objective of advising the Main Commission of the ICRP on the possible implications for radiological protection of emerging views on genetic susceptibility to cancer (Chapter 1). Chapter 2 considers DNA damage and its processing/repair after ionising radiation and serves principally to demonstrate that a few rare cancer-prone, human recessive genetic disorders show DNA repair deficiency and profound increases in radiosensitivity. Less dramatic changes in radiosensitivity are also apparent in a wider range of such disorders. The cellular mechanisms that underly the association between DNA damage processing and tumorigenesis are discussed. Chapter 3 reviews the mechanisms and genetics of solid tumours illustrating the ways in which mutations in proto-oncogenes, tumour suppressor genes together with those in DNA repair and cell cycle control genes can contribute to tumour development. Specific examples are given of how germ line mutation of such genes can predispose to familial cancer. It is judged that up to 5% of all solid tumours have a recognisable genetic component. Heritable organ-specific effects are most usual and cancers of the breast and colon tend to show the most obvious genetic components. Clearly discernible genetic effects are seen when rare dominant germ line mutations express strongly as familial cancer (high penetrance mutations), but the existence of perhaps less rare low penetrance mutations and gene-gene interactions are recognised but not well understood. Chapter 4 considers the mechanisms and genetics of lympho-haemopoietic tumours. Specific chromosomal translocations and proto-oncogene activation events are much more frequent in human leukaemia/lymphoma than in solid tumours. Genetic predisposition to leukaemia/lymphoma is found in a number of non-familial recessive genetic disorders of DNA processing and/or chromosomal instability. Familial manifestation of susceptibility to these tumours is, however, extremely rare. The genetic component, although poorly defined, is judged to be less than that of solid tumours and expressed largely in childhood. Chapter 5 reviews and discusses limited data that comment upon tumorigenic radiosensitivity in cancer-prone genetic conditions. From knowledge of the fundamental processes involved it is judged that in most, but not all, cases genetic susceptibility to spontaneous tumours will be accompanied by a greater-than-normal risk after radiation. A review of epidemiological, clinical and experimental data relevant to this issue suggests that although a wide range of different sensitivities may be involved, a factor of 10 increase in sensitivity broadly accords with the limited human data available. This interim judgement of a factor of 10 increase in radiation risk in such human genetic disorders is made for the purposes of illustrative modelling and calculation. In addition, specific attention is given to breast cancer risk in heterozygotes for the radiosensitive human disorder, ataxia-telangiectasia; this association, while in no way discounted, is judged to be less strong than that claimed by some. Chapter 6 discusses and develops computational modelling procedures that aim to describe the impact of genetic factors on radiation-tumorigenesis in human populations. Estimates of the prevalence of known cancer-prone genetic disorders are made but breast cancer susceptibility is used to illustrate the application of the model developed. The most important message to emerge from this work is that, even at an assumed high level of radiation sensitivity, the prevalence of familial (high penetrance) genetic disorders in the population is too low (<1%) for there to be a significant impact on risk in typical human populations. In principle, however, there is the potential for such impact in atypical inbred sub-populations where these mutations can be more common. (ABSTRACT TRUNCATED)
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PMID:Genetic susceptibility to cancer. ICRP publication 79. Approved by the Commission in May 1997. International Commission on Radiological Protection. 1040 27

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