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)

Ataxia telangiectasia (A-T) is a human disorder that results in a number of clinical symptoms, including cerebellar degeneration and increased cancer predisposition. Recently the gene that is defective in A-T has been cloned and designated ATM. Here, we describe the production of antisera raised against the approximately 350 kDa ATM protein. Antisera specificity is confirmed by them recognising a approximately 350 kDa polypeptide in wild-type cells but not in A-T cells containing mutations that truncate ATM upstream of the antibody binding sites. We show that ATM is almost exclusively nuclear and is expressed in all cell lines and tissues analysed. However, ATM levels are not regulated in response to u.v. or ionising radiation. These data are consistent with ATM being a component of the DNA damage detection apparatus rather than being an inducible downstream effector of the DNA damage response. In addition, we analyse ATM protein expression in a variety of A-T patients. Strikingly, ATM expression is reduced drastically or absent in all patients analysed, including those predicted to express proteins that should be detected by our antisera. Thus, the A-T phenotype may result not only from mutations that disrupt functional domains of ATM, but also from mutations that destabilise the ATM mRNA or protein. Finally, we report that a group of patients displaying an intermediate A-T phenotype express low levels of apparently full-length ATM. This suggests that the ATM pathway is partially active in these individuals and that there is a correlation between levels of residual ATM expression and disease severity.
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PMID:Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. 900 Jan 45

The present study was undertaken to examine the effects of volume overload on cardiac gene expression and the possible role of angiotensin AT1 receptor in such expression. Cardiac volume overload was prepared by abdominal aortocaval shunt in rats. Rats with aortocaval shunt were treated with 1) vehicle, 2) an angiotensin AT1 receptor antagonist, CS-866 (10 mg/kg/d), or 3) an angiotensin-converting enzyme inhibitor, temocapril (10 mg/kg/d), for 7 days. Cardiac tissue mRNA was measured by Northern blot analysis with specific probes. Aortocaval shunt not only caused cardiac hypertrophy but also upregulated the gene expression of atrial natriuretic polypeptide, collagen III, and downregulated Ca(2+)-ATPase expression in the left ventricle. These changes were prevented by treatment with CS-866, while temocapril failed to normalize left ventricular Ca(2+)-ATPase expression. Unlike the left ventricle, the significant downregulation of alpha-myosin heavy chain and transforming growth factor-beta 3 by aortocaval shunt was observed in the right ventricle, and CS-866 normalized this decreased expression of transforming growth factor-beta 3. The left and right atria showed increased expression of collagen type I as well as of collagen type III and atrial natriuretic polypeptide, and these increases were more effectively prevented by CS-866 than by temocapril. Thus, the effects of cardiac volume overload on cardiac performance-related gene expression differ between the ventricles and atria. Our results suggest that AT1 receptor partially contributed to volume overload-induced changes in cardiac gene expression and that AT1 receptor antagonists and angiotensin-converting enzyme inhibitors have different effects in this model of cardiac hypertrophy.
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PMID:Effects of angiotensin AT1 receptor antagonist on volume overload-induced cardiac gene expression in rats. 922 Feb 78

The isolation and molecular characterization of the Ang II/AVP receptor elucidates the structure of a novel dual receptor coupled to adenylate cyclase and responding with equal sensitivity to Ang II and AVP. The cloning strategy in conjunction with site directed mutagenesis have permitted the delineation of the Ang II and AVP binding domains within the receptor polypeptide. Pharmacological characterization of the receptor defines the AngII/AVP receptor as a novel AT1/V2 type of receptor. The renal immunocytochemical distribution of the Ang II/AVP receptor to the outer medullary thick ascending limb tubules and inner medullary collecting ducts suggests a prominent role in renal tubular sodium and fluid reabsorption.
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PMID:Identification of a novel dual angiotensin II/vasopressin receptor. 985 77

1. Regional haemodynamic alterations caused by hypertonic NaCl solution (Hi-Salt; 10%, 10 microL) injected intracerebroventricularly (i.c.v.) were investigated by using radioactive microspheres in anaesthetized rats. 2. Intracerebroventricular injections of Hi-Salt increased regional vascular resistance of visceral organs, including the kidney, and elevated plasma levels of vasopressin. 3. Intracerebroventricular pretreatment with TCV-11974 (50 micrograms/10 microL/nat), an angiotensin AT1 receptor antagonist, attenuated the pressor response and vasopressin release to subsequently injected Hi-Salt, but did not affect regional haemodynamic effects of i.c.v. Hi-Salt on vascular resistance. 4. In contrast, i.c.v. pretreatment with atrial natriuretic polypeptide (ANP) or type-C natriuretic polypeptide (CNP) almost completely abolished the haemodynamic changes and vasopressin release caused by i.c.v. Hi-Salt. 5. The present findings indicate that a natriuretic family in the brain may be involved to a great degree in the central regulation of salt-induced hypertension in rats, while brain angiotensin II is likely to participate only in vasopressin release.
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PMID:Brain atrial natriuretic peptide family abolishes cardiovascular haemodynamic alterations caused by hypertonic saline in rats. 1049 57

The human neurodegenerative and cancer predisposition condition ataxia-telangiectasia is characterized at the cellular level by radiosensitivity, chromosomal instability, and impaired induction of ionizing radiation-induced cell cycle checkpoint controls. Recent work has revealed that the gene defective in ataxia-telangiectasia, termed ATM, encodes an approximately 350-kDa polypeptide, ATM, that is a member of the phosphatidylinositol 3-kinase family. We show that ATM binds DNA and exploit this to purify ATM to near homogeneity. Atomic force microscopy reveals that ATM exists in two populations, with sizes consistent with monomeric and tetrameric states. Atomic force microscopy analyses also show that ATM binds preferentially to DNA ends. This property is similar to that displayed by the DNA-dependent protein kinase catalytic subunit, a phosphatidylinositol 3-kinase family member that functions in DNA damage detection in conjunction with the DNA end-binding protein Ku. Furthermore, purified ATM contains a kinase activity that phosphorylates serine-15 of p53 in a DNA-stimulated manner. These results provide a biochemical assay system for ATM, support genetic data indicating distinct roles for DNA-dependent protein kinase and ATM, and suggest how ATM may signal the presence of DNA damage to p53 and other downstream effectors.
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PMID:Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM. 1050 Jan 42

ATM, the gene product mutated in Ataxia Telangiectasia (A-T) encodes a 350-kDa protein involved in the regulation of several cellular responses to DNA breaks. We used a degenerate PCR-based strategy to isolate a partial clone of X-ATM, the Xenopus homologue of human ATM. Sequence analysis and confirmed that the clone was most closely related to human ATM. Xenopus ATM protein (X-ATM) is 85% identical to human ATM within the kinase domain and 71% identical over the carboxyl-terminal half of the protein. Polyclonal antibodies raised against recombinant X-ATM are highly specific for the ATM protein and recognize a single polypeptide of 370-kDa in oocytes, embryos, egg extracts and a Xenopus cell line. We found that X-ATM was expressed maternally in eggs and as early as stage II pre-vitellogenic oocytes, and the protein and mRNA were present at relatively constant levels throughout development. Subcellular fractionation showed that the protein was nuclear in both the female and male germlines. The level of X-ATM protein did not change throughout the meiotic divisions or the synchronous mitotic cycles of cleavage stage embryos. In addition, we did not observe any change in the level or mobility of X-ATM protein following gamma-irradiation of embryos. Finally, we also demonstrated that X-ATM was present in a high molecular weight complex of approximately 500 kDa containing the X-ATM protein and other, as yet unidentified component(s).
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PMID:Isolation and characterization of Xenopus ATM (X-ATM): expression, localization, and complex formation during oogenesis and early development. 1059 8

Ataxia-telangiectasia (A-T) is a genetic disorder characterized by a progressive ataxia, immunodeficiency, neurological abnormalities, hypersensitivity to ionizing radiation, and predisposition to cancer. The gene responsible for A-T (ATM) has been cloned and shown to code for a 350 kDa polypeptide containing 3,056 amino acid residues. Detection of ATM mutations for laboratory diagnosis of A-T is laborious and not practical, unless there are common mutations in a population. We describe here immunoblot analysis for the detection of ATM in seven Japanese A-T patients from five families and in controls using ATM3BA antibody. ATM protein was routinely and clearly detected in Epstein-Barr virus (EBV)-transformed or phytohemagglutinin (PHA)-stimulated lymphoblasts from controls. However, it could not be detected consistently in unstimulated peripheral blood mononuclear cells (PBMCs) from controls. We also detected ATM protein in control fibroblasts, but the background was relatively higher than in control lymphoblasts. ATM protein was not detected or dramatically decreased in EBV-transformed lymphoblasts from all seven patients tested and in fibroblasts from one patient. Immunoblot analysis using EBV-transformed or PHA-stimulated lymphoblasts represents a useful approach for laboratory diagnosis for A-T. The latter is especially preferable since it takes only 3 days to obtain sufficient cells for analysis.
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PMID:Immunoblot analysis for laboratory diagnosis of ataxia-telangiectasia: use of Epstein-Barr virus-transformed or phytohemagglutinin-stimulated lymphoblasts for detection of ATM protein. 1078 Jul 98

A new isogene for acyl-(acyl-carrier-protein):glycerol-3-phosphate acyltransferase (GPAT; EC 2.3.1.15) in squash has been cloned and the gene product was identified as oleate-selective GPAT. Using PCR primers that could hybridise with exons for a previously cloned squash GPAT, we obtained two PCR products of different size: one coded for a previously cloned squash GPAT corresponding to non-selective isoforms AT2 and AT3, and the other for a new isozyme, probably the oleate-selective isoform AT1. Full-length amino acid sequences of respective isozymes were deduced from the nucleotide sequences of genomic genes and cDNAs, which were cloned by a series of PCR-based methods. Thus, we designated the new gene CmATS1;1 and the other one CmATS1;2. Genome blot analysis revealed that the squash genome contained the two isogenes at non-allelic loci. AT1-active fractions were partially purified, and three polypeptide bands were identified as being AT1 polypeptides, which exhibited relative molecular masses of 39.5-40.5 kDa, pI values of 6.75-7.15, and oleate selectivity over palmitate. Partial amino-terminal sequences obtained from two of these bands verified that the new isogene codes for AT1 polypeptides.
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PMID:A second gene for acyl-(acyl-carrier-protein): glycerol-3-phosphate acyltransferase in squash, Cucurbita moschata cv. Shirogikuza(*), codes for an oleate-selective isozyme: molecular cloning and protein purification studies. 1113 24

Work reported in this chapter describes the potential role of relaxin in resetting cardiovascular thresholds in pregnant rats. Relaxin, a polypeptide produced primarily by the ovary in pregnant animals in many species, is also produced in the brain. Exogenous administration of relaxin into the brain causes a profound drinking response which is negated by pretreatment with a specific monoclonal antibody to rat relaxin when the antibody is injected into the brain. Neutralizing the action of endogenous brain relaxin in pregnant rats also blocks the normal increase in drinking that is observed in rats at night during the second half of pregnancy. Relaxin acts through the forebrain angiotensin system at the level of the subfornical organ (an important interface between the blood, the brain and the cerebrospinal fluid) as blockade of the angiotensin II receptor action negates several central actions of relaxin. Expression of angiotensin II AT1 receptors in the subfornical organ increases in parallel with the increase in circulating relaxin seen in the second half of pregnancy. Neutralizing the effects of endogenous brain relaxin, using central injections of the monoclonal antibody, blocks this increase in the expression of angiotensin II AT1 receptors in subfornical organ. These data imply that relaxin in the brain may act to affect central cardiovascular thresholds in rats and this may be important for the normal physiology of pregnancy.
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PMID:Relaxin and drinking in pregnant rats. 1158 33

The tumour-suppressor protein BRCA1 mediates its biological functions by interacting with cellular factors such as the CtIP polypeptide, a substrate for the ATM (for 'ataxia telangiectasia mutated') protein kinase. Li et al. report that the BRCA1-CtIP interaction is disrupted by ionizing radiation and by other genotoxic stresses that induce phosphorylation of CtIP by ATM kinase, and that this dissociation of the BRCA1-CtIP complex in turn modulates the transcription of DNA-damage-response genes. We have shown that the BRCA1-binding domain of CtIP (amino-acid residues 133-369) is distal to the sites that are phosphorylated by ATM kinase (residues S664 and S745). We now show that the BRCA1-CtIP complex is stable in irradiated cells, and that the phosphorylated isoforms of CtIP that are induced by ionizing radiation still interact in vivo with BRCA1. We conclude that disruption of the BRCA1-CtIP complex cannot account for induction of DNA-damage-response genes in the way proposed by Li et al.
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PMID:Effect of DNA damage on a BRCA1 complex. 1168 34


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