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)

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

Neocarzinostatin (NCS) is an acidic, single-chain polypeptide of 109 amino acids that has shown some antitumor activity in clinical trials. NCS is mutagenic in recA+ strains of Escherichia coli, but not in recA strains; on the other hand, a defect in the nucleotide-excision-repair pathway has no effect on the mutagenicity of NCS in E. coli. Similar results are seen in mammalian cells. Excision-repair-deficient xeroderma pigmentosum (XP) cells repair NCS-induced DNA damage at the same rate as repair-proficient XP heterozygotes, and X-ray-sensitive ataxia telangiectasia fibroblasts are also sensitive to NCS. I have investigated the mutagenicity of NCS in the ad-3 forward-mutation test in nucleotide excision-repair-sufficient and -deficient heterokaryons of Neurospora crassa. Resting conidia from a repair-sufficient strain, H-12, and a nucleotide-excision-repair-deficient strain (uvs-2) H-59, were exposed to NCS. These conidia were assayed for survival and ad-3 forward mutation. The results show that H-59 is more sensitive to the killing and mutagenic activities of NCS than is H-12. These data indicate, in contrast to E. coli and mammalian cells, that the nucleotide-excision-repair pathway of N. crassa does repair NCS-induced lesions. In other experiments, ad-3 mutants induced by NCS in H-59 were characterized to determine the spectrum of NCS-induced mutation. The results show that NCS induces both intracistronic mutations and multilocus deletions in H-59.
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PMID:Mutagenicity of neocarzinostatin in Neurospora crassa. 623 65

Angiotensin converting-enzyme inhibitors (alacepril and imidapril) or an AT1-receptor antagonist (SC-52458) was administered to 10-week-old spontaneously hypertensive rats (SHR) for 7 days, and cardiac mRNA levels for contractile proteins and atrial natriuretic polypeptide (ANP) were comprehensively measured. The expression of skeletal alpha-actin and ANP was selectively enhanced in the heart of vehicle-treated SHR compared with Wistar-Kyoto rats (WKY), thereby suggesting that the phenotypic modulation of myocytes occurred at the early stage of hypertension. The above-mentioned three drugs similarly suppressed these enhanced gene expressions, nearly to the control levels. In contrast, although the treatment with hydralazine lowered the blood pressure of SHR similarly, hydralazine did not suppress ANP expression at all and only partially suppressed skeletal alpha-actin. Moreover, alacepril did not affect these gene expressions in WKY. Thus, AT1 receptor may be crucial for phenotypic modulation in the heart of SHR.
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PMID:Cardiac hypertrophy-related gene expression in spontaneously hypertensive rats: crucial role of angiotensin AT1 receptor. 774 53

1. Regional haemodynamic responses to the homologous peptides, pituitary adenylate cyclase-activating peptide (1-27) (PACAP27) and vasoactive intestinal polypeptide (VIP) were assessed by giving 20 min infusions (1.5-15 nmol kg-1 h-1) in conscious, chronically-instrumented, Long Evans rats. 2. PACAP27 caused dose-dependent depressor and tachycardic effects associated with renal, mesenteric and hindquarters vasodilatations, although only in the latter vascular bed was there a sustained increase in flow. 3. VIP caused dose-dependent depressor and tachycardic effects that were not significantly different from those caused by equimolar doses of PACAP27. However, the hindquarters vasodilator effects of VIP (at 7.5 and 15 nmol kg-1 h-1) were greater than those of PACAP27 (at the same doses), and accompanied by reductions in renal and mesenteric flows and conductances. 4. In the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 11 mumol kg-1 h-1), there was significant inhibition of the hindquarters vasodilator effects of PACAP27 and VIP (at 7.5 and 15 nmol kg-1 h-1). Under these circumstances the renal and mesenteric vasoconstrictor effects of VIP were abolished. 5. The beta 2-adrenoceptor antagonist, ICI 118551 (670 nmol kg-1 bolus, 335 nmol kg-1 h-1 infusion), reduced the matched hindquarters vasodilator responses to PACAP27 (15 nmol kg-1 h-1) and VIP (7.5 nmol kg-1 h-1), and also abolished the renal vasoconstrictor effects of VIP. 6. The AT1-receptor antagonist, losartan potassium (20 mumol kg-1), had no significant effect on the haemodynamic response to PACAP27 (15 nmol kg-1 h-1), but augmented the hypotensive action of VIP (7.5 nmol kg-1 h-1). This influence of losartan was associated with conversion of the renal and mesenteric vasoconstrictor effect of VIP to vasodilatation. 7. Our findings show that similar changes in mean systemic arterial blood pressure in response to PACAP27 and VIP conceal substantial differences in their regional haemodynamic actions. Although the hindquarters vasodilator effects of both peptides involve NO- and Beta2-adrenoceptor-mediated mechanisms,it appears that activation of the renin-angiotensin system contributes significantly to the haemodynamic effects of VIP, but not to those of PACAP27.
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PMID:Regional haemodynamic responses to pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide in conscious rats. 791 21

Proliferation of the rat intestinal epithelial cell-line, RIE-1, has previously been shown to be stimulated by certain polypeptide growth factors acting via receptors that possess intrinsic tyrosine kinase activity. In this study, we show that the octapeptide hormone angiotensin II (AII), apparently acting through the AT1 G-protein-coupled receptor, is also a mitogen for RIE-1 cells. Maximal stimulation of DNA synthesis and cellular proliferation occurred at an AII concentration of 10-100 nM, with half-maximal stimulation at 1 nM. The mitogenic response to AII was completely inhibited by the AT1 angiotensin-receptor antagonist, DuP753, but not by the AT2-receptor antagonist, PD123319. The early signalling responses activated by AII in RIE-1 cells include increased production of inositol phosphates, a transient increase in the intracellular concentration of free calcium, an activation of protein kinase C, and a rapid change in the pattern of cellular protein-tyrosine phosphorylation. These results implicate an activation of the inositol lipid signalling pathway via the AT1 receptor subtype in the AII-stimulated mitogenic response of this normal epithelial cell line.
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PMID:Activation of AT1 angiotensin receptors induces DNA synthesis in a rat intestinal epithelial (RIE-1) cell line. 794 4

The angiotensin II receptors of human myometrial tissue were characterized using ligand binding, cross-linking with radioactive label, detergent solubilization and partial purification by lectin-affinity chromatography. Human myometrial membrane preparations contained variable amount (5-650 fmol/mg protein) of high affinity (Kd = 44-65 pM) binding sites for 125I-CGP42112, a ligand specific for the AT2 subtype of angiotensin II receptors. Competition studies with AT1-specific and AT2-specific compounds indicated that angiotensin II receptors on these membranes were exclusively of the AT2 subtype. The binding sites for 125I-CGP42112 were efficiently solubilized by the detergent Chaps, albeit with a marked decrease in affinity (Kd = 1.2 nM). The proteins in the myometrial membrane preparation were cross-linked to 125I-[Sar1, Ile8]angiotensin II (Sarile) with disuccinimidyl suberate. When low concentrations of cross-linker were used, a single radiolabelled band of about 66-70 kDa was revealed on SDS/PAGE. At higher concentrations additional bands of about 105-120 kDa and 200 kDa were labelled. The 66-70-kDa and 105-120-kDa bands were separated by electroelution of SDS/PAGE gel slices and submitted to trypsin cleavage. The tryptic-peptide maps were identical for both products, suggesting that the additional bands are homodimers and trimers of the labelled polypeptide. The Chaps-solubilized receptor was retained on wheat-germ-agglutinin-Sepharose and specifically eluted by the competing sugar triacetylchitotriose, leading to a fivefold purification factor. Treatment of the 125I-Sarile-labelled protein with N-glycanase caused a shift in its apparent molecular mass on SDS/PAGE from 66-70 kDa to 33 kDa.
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PMID:Characterization of a membrane glycoprotein having pharmacological and biochemical properties of an AT2 angiotensin II receptor from human myometrium. 814 46

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency radiation sensitivity, and cancer predisposition. A-T heterozygotes are moderately cancer prone. The A-T gene, designated ATM, was recently identified in our laboratory by positional cloning, and a partial cDNA clone was found to encode a polypeptide with a PI-3 kinase domain. We report here the molecular cloning of a cDNA contig spanning the complete open reading frame of the ATM gene. The predicted protein of 3056 amino acids shows significant sequence similarities to several large proteins in yeast, Drosophila and mammals, all of which share the PI-3 kinase domain. Many of these proteins are involved in the detection of DNA damage and the control of cell cycle progression. Mutations in their genes confer a variety of phenotypes with features similar to those observed in human A-T cells. The complete sequence of the ATM gene product provides useful clues to the function of this protein, and furthers understanding of the pleiotropic nature of the A-T mutations.
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PMID:The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. 858 78

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.
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PMID:Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats. 876 77

The recently cloned ATM gene is mutated in patients with ataxia telangiectasia, but its biological functions remain to be experimentally determined. Structural analysis has revealed ATM sequence similarities to the catalytic domains of phosphatidyl-3 kinase and other members of this family of yeast and mammalian proteins. Rabbit polyclonal antibodies raised against polypeptide regions unique to the COOH terminus and to the NH2 terminus of the published ATM sequence confirm ATM as M(r) approximately 350,000 protein in normal cells, which is missing in AT cells. Immunoprecipitated protein(s) is capable of phosphorylating I kappa B-alpha in an in vitro kinase assay. However, we did not observe a phosphatidyl-3 kinase or a DNA-dependent protein kinase function by ATM immunoprecipitates. These data support a protein kinase activity for ATM and suggest a role in NF-kappa B activation.
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PMID:ATM gene product phosphorylates I kappa B-alpha. 898 33

Ataxia-telangiectasia (AT) is an autosomal recessive disease characterized by neurodegeneration and immunodeficiency. Hypersensitivity to radiation and chromosome instability are the biological markers of this disease. The gene responsible for AT (ATM), has been identified on chromosome 11q22-23; it encodes a large polypeptide partially homologous to the phosphatidylinositol (PI) 3-kinase family. PI 3-kinase is a protein family playing an important role in the prevention of apoptosis. In order to investigate the apoptosis pathway, we tested peripheral blood cells from AT patients and controls exposed to 2-deoxy-D-ribose (dRib), a reducing sugar that induces apoptosis in human quiescent lymphocytes, probably through oxidative damage. Our results show that the response to dRib-induced apoptosis is significantly more elevated in AT cells than in control cells, suggesting that the apoptotic process plays a role in the pathogenesis of AT disease.
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PMID:Increased apoptotic response to 2-deoxy-D-ribose in ataxia-telangiectasia. 899 14


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