Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most cell types, including vascular smooth muscle cells and rat kidney mesangial cells, are controlled mainly by two types of cell surface receptors: (a) single membrane-spanning tyrosine kinase receptors for growth factors and (b) seven-transmembrane G-protein linked receptors for vasoactive peptides such as angiotensin II, vasopressin, and endothelin. These vasoactive peptide hormones also act as growth factors in normal and abnormal cell development. However, in contrast to the growth factor receptors (e.g., epidermal growth factor receptor and platelet-derived growth factor receptor), the G-protein linked receptors, such as the angiotensin II AT1 receptor, lack cytoplasmic tyrosine kinase domains. Nevertheless, angiotensin II has recently been demonstrated to cause increased tyrosine phosphorylation of numerous proteins in several cellular systems. For example, angiotensin II has been reported to induce the tyrosine phosphorylation of the gamma-isoform of phospholipase C, pp120, pp125FAK, and members of the janus kinase/signal transducer and activator of transcription pathway. Furthermore, angiotensin II seems to modulate the activity of the soluble cytoplasmic tyrosine kinase pp60c-src, and this tyrosine kinase has been implicated in the phosphorylation of some of the above proteins. Understanding the biochemistry of tyrosine phosphorylation involved in G-protein coupled receptors, such as the AT1 receptor, may therefore lead to the development of new pharmacological interventions important in cardiovascular diseases.
J Mol Med (Berl) 1996 Feb
PMID:The role of tyrosine phosphorylation in angiotensin II mediated intracellular signaling and cell growth. 882 Apr 3

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.
Hum Mol Genet 1996 Apr
PMID:Predominance of null mutations in ataxia-telangiectasia. 884 35

Stimulation of cultured rat thoracic aorta vascular smooth muscle cells (VSMCs) with 100 nM angiotensin II (Ang II) reduces angiotensin receptor type 1 (AT1-R) gene expression. mRNA levels are reduced to approximately 30% of control levels 4 hr after the addition of Ang II to the culture medium. The loss of mRNA remains sustained for up to 24 hr after the addition of Ang II. The half-life of the AT1-R mRNA is approximately 2 hr in cells treated with a single dose of 100 nM Ang II. This represents a 3-fold reduction from its half-life of 6 hr in nonstimulated cells, as assessed by treatment with 5,6-dichlorobenzimidazole or actinomycin D to block transcription. Thus, the AT1-R mRNA is moderately unstable in VSMC and destabilized further by treatment with Ang II. Ang II-induced AT1-R mRNA destabilization is prevented by pretreatment with transcriptional inhibitors or the protein synthesis inhibitor cycloheximide, suggesting that Ang II-induced AT1-R mRNA destabilization requires the induction of an unknown factor or factors that are postulated to mediate this effect. AT1-R mRNA levels decrease more rapidly in vitro from a polyribosomal fraction isolated from VSMC exposed for 2 hr to 100 nM Ang II compared with that from vehicle-treated cells, suggesting that polyribosomal-associated AT1-R mRNA is at least one site of action for the mRNA destabilization effect of Ang II. Ang II stimulation induces a complex of polyribosomal proteins that bind specifically in the distal 350 bases of the AT1-R mRNA. Regulation of mRNA stability accounts in part for modulation of AT1-R gene expression by Ang II in VSMCs, and Ang II-induced AT1-R mRNA polyribosomal binding proteins are associated with this phenomenon.
Mol Pharmacol 1996 Oct
PMID:Enhanced angiotensin receptor type 1 mRNA degradation and induction of polyribosomal mRNA binding proteins by angiotensin II in vascular smooth muscle cells. 886 18

Bovine adrenal cortical cells (BAC) express corticotropin (ACTH) and angiotensin II (AngII) receptors (AT1 subtype), which are coupled to adenylate cyclase and phosphoinositide pathways, respectively. The coupling of AT1 to phosphoinositide breakdown is mainly pertussis toxin-insensitive suggesting that this receptor is coupled to Gaeq/Gae11. In the present work we have demonstrated that BAC express G alpha q and G alpha 11 mRNA and proteins, and their variation during culture as well as their regulation by ACTH and AngII is different. ACTH enhanced G alpha q mRNA levels mainly by increasing the transcription rate. In addition, ACTH increased both G alpha q and G alpha 11 proteins without changing their half-lives. In contrast, AngII reduced both G alpha q mRNA and protein and increased G alpha 11 mRNA but not G alpha 11 protein. The decrease of G alpha q mRNA levels was mainly due to a marked reduction of its half-life. These changes in G alpha q/G alpha 11 proteins induced by both hormones were associated with an enhanced AngII-induced inositol phosphate accumulation, more marked after stimulation with ACTH than after AngII pretreatment. In summary, the present results demonstrated that BAC express both G alpha q and G alpha 11 and their regulations are different and in contrast to other cell types these regulations do not involve changes in the half-life of G alpha q/G alpha 11 proteins.
Mol Cell Endocrinol 1996 Jul 23
PMID:Expression and regulation of G alpha q and G alpha 11 mRNAs and proteins in bovine adrenal cells. 886 67

The present study was undertaken to determine whether trandolaprilat, an active form of angiotensin I converting enzyme (ACE) inhibitor, may improve ischemia/reperfusion-induced contractile dysfunction and metabolic derangement of isolated rat hearts. Ischemia (25 min) and subsequent 60-min reperfusion resulted in a small recovery of post-ischemic left ventricular developed pressure (LVDP), a sustained increase in left ventricular end-diastolic pressure, an increase in the release of creatine kinase and ATP metabolites from the perfused heart, and changes in myocardial sodium, potassium, calcium and magnesium contents. Treatment with 10-100 microM of trandolaprilat for the last 10 min of pre-ischemia recovered approximately 50-90% of pre-ischemic LVDP during reperfusion, whereas that with 30-100 microM of enalaprilat restored approximately 55-65% of the pre-ischemic LVDP. Treatment with either trandolaprilat or enalaprilat at these concentrations attenuated the release of creatine kinase and ATP metabolites into the perfusate during reperfusion. Treatment with 30 microM trandolaprilat suppressed ischemia/reperfusion-induced changes in myocardial ion content. Treatment with bradykinin during the last 10 min of pre-ischemia also resulted in a post-ischemic contractile recovery with a degree similar to that of the trandolaprilat-treated hearts. E4177, an AT1-antagonist, showed no effect on ischemia/reperfusion-induced changes in cardiac parameters. The enhancement of post-ischemic contractile recovery by the ACE inhibitor was abolished by treatment with either Hoechst 140, a bradykinin (BK2) antagonist, or diclofenac, a cyclooxygenase inhibitor. These results suggest that trandolaprilat is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts and altered BK metabolism is, at least in part, involved in this effect.
J Mol Cell Cardiol 1996 Aug
PMID:Beneficial effects of angiotensin I converting enzyme inhibitor on post-ischemic contractile function of perfused rat heart. 887 76

The regulation of the AT1 receptor gene was studied in neonatal cardiomyocytes and fibroblasts in vitro. Incubation with angiotensin II (Ang II) resulted in a time-dependent and dose-dependent decrease in AT1 mRNA levels in both cardiomyocytes and fibroblasts. Coincubation with Ang II and the specific AT1 antagonist losartan prevented the decrease in AT1 mRNA whereas the AT2 antagonist PD123319 was ineffective in preventing the decrease in AT1 mRNA. Because Ang II is known to decrease cAMP levels in cardiomyocytes, the role of cAMP in the regulation of the AT1 gene was examined. Treatment with the adenylyl cyclase stimulant forskolin or the cAMP stereoisomer Sp-cAMPS increased AT1 mRNA levels or prevented the Ang II mediated decrease in AT1 mRNA levels. The role of calcium in the regulation of the AT1 gene was determined by incubation with the calcium ionophores A23187 and ionomycin (0.0625-1 microM) which resulted in a profound, dose-dependent decrease in AT1 mRNA levels. Treatment with BAPTA, an intracellular chelator of calcium, prevented the Ang II-mediated decrease in AT1 mRNA. Therefore Ang II is a potent negative regulator of the AT1 gene in cardiomyocytes and fibroblasts via the AT1 receptor. This Ang II mediated decrease in AT1 mRNA is mediated by two complementary mechanisms involving cAMP and intracellular calcium.
J Mol Cell Cardiol 1996 Aug
PMID:AT1 receptor gene regulation in cardiac myocytes and fibroblasts. 887 82

Angiotensin II has two major receptor subtypes, designated AT1 and AT2. Both have been detected in the heart of several species, but most of the known functions of angiotensin II seem to be mediated through the AT1 receptor. The major objective of this study was to specify the cell type on which the AT2 receptor is located in the atrium of human heart. Right atrial biopsies from patients with coronary artery disease were tested in membrane binding assays and found to contain high levels of angiotensin II receptor (820 +/- 175 fmol/mg), 82 +/- 2% of which was of the AT2 subtype. Cryostat sections of these biopsies were incubated with 125I-[Sar1,Ile8] angiotensin II in the presence of selective concentrations of the cold ligands losartan and CGP 42112A to detect the subtypes using microscopic autoradiography. High local densities of the AT2 receptor were observed. Comparison of the labelling patterns thus obtained with adjacent sections stained for vimentin, collagen, neurofilaments or acetylcholinesterase revealed that the high densities of AT2 receptor were always associated with fibrous tissue. However, the AT1 receptor was in general evenly distributed over the tissue at low concentrations. Higher local concentrations of this receptor subtype were observed on nervous tissue. The present finding of high densities of the AT2 receptor on fibroblasts at sites of fibrosis may have important clinical implications. Further studies to elucidate the function of this receptor subtype in the heart are therefore essential and the clinical consequences of the use of AT1 antagonists on post-infarction remodelling should be investigated.
J Mol Cell Cardiol 1996 Aug
PMID:Localization of the angiotensin II receptor subtypes in the human atrium. 887 88

Angiotensin II (ANG II) has been implicated in cell growth and differentiation. We investigated the effect of AT2 receptor stimulation on proliferation and morphological differentiation in cells of neuronal origin by using the pheochromocytoma derived cell line, PC12W. ANG II (10(-8)-10(-6) M) inhibited fetal calf serum (FCS)-induced cell proliferation in a concentration dependent manner. In half of the experiments, the epidermal growth factor (EGF) exerted a mitogenic action which was concentration-dependently inhibited by ANG II. In the other half of the experiments, EGF had an antimitogenic effect which was further enhanced by ANG II (maximally at 10(-6) M). Treatment with nerve growth factor (NGF) induced an inhibition of [3H]thymidine incorporation, which was enhanced by ANG II, maximally 25% at the highest concentration. The effects of ANG II on [3H]thymidine incorporation were reflected by those on cell number and were prevented by the AT2 receptor antagonist, PD123177, but not influenced by the AT1 receptor antagonist, losartan. The ANG II-induced inhibition of cell proliferation was paralleled by morphological differentiation in response to daily treatment with ANG II. ANG II also enhanced low-dose NGF-induced neurite formation. Again, these effects of ANG II were abolished by the AT2 receptor antagonist, PD123177. Our data in PC12W cells show that the AT2 receptor not only inhibits growth factor-induced proliferation and enhances the NGF-mediated growth arrest but also induces morphological differentiation in cells of neuronal origin. These findings strongly support the hypothesis that the AT2 receptor promotes differentiation in neuronal cells.
Mol Cell Endocrinol 1996 Aug 30
PMID:The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells. 889 48

In an earlier report we showed that the 5' end of the gene for ataxia telangiectasia ATM is within 700 bp of the 5' end of a novel gene E14, and suggested that the CpG island that separates these genes functions as a bidirectional promoter. We have now determined the complete amino acid sequence of the E14 protein, defined the exon/intron structure of the gene and estimate that the complete gene is more than 55 kb in length. The E14 gene appears to be a housekeeping gene that is expressed in all tissues, including all parts of the brain. The E14/ATM promoter organisation is conserved in man, monkey and mouse, although the mouse promoter is more compact and appears to lack two of the four putative Sp1 boxes found in the human promoter. Reporter gene constructs showed that the human and mouse E14/ATM promoters were indeed bidirectional, that the ATM side of the human promoter was three times stronger than the E14 side, and that the mouse promoter (in human cells) directed transcription with equal efficiency in both directions, but at a lower level than the human promoter. Analysis of a small number of A-T patients for mutations in the promoter region or the E14 coding sequence did not provide evidence to suggest that E14 contributes to the A-T phenotype.
Hum Mol Genet 1996 Nov
PMID:A gene transcribed from the bidirectional ATM promoter coding for a serine rich protein: amino acid sequence, structure and expression studies. 892 7

The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency and cancer predisposition. A-T carriers were reported to be moderately cancer-prone. A wide variety of A-T mutations, most of which are unique to single families, were identified in various ethnic groups, precluding carrier screening with mutation-specific assays. However, a single mutation was observed in 32/33 defective ATM alleles in Jewish A-T families of North African origin, coming from various regions of Morocco and Tunisia. This mutation, 103C-->T, results in a stop codon at position 35 of the ATM protein. In keeping with the nature of this mutation, various antibodies directed against the ATM protein failed to defect this protein in patient cells. A rapid carrier detection assay detected this mutation in three out of 488 ATM alleles of Jewish Moroccan or Tunisian origin. This founder effect provides a unique opportunity for population-based screening for A-T carriers in a large Jewish community.
Hum Mol Genet 1996 Dec
PMID:Ataxia-telangiectasia: founder effect among north African Jews. 896 60


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