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)

Our laboratory has reported previously that a unique binding site specific for the hexapeptide angiotensin (A)II(3-8), now referred to as AIV, is present in a number of tissues including bovine adrenal gland, rabbit and guinea pig heart and guinea pig kidney, liver, lung, uterus and brain. The present results extend previous findings in the guinea pig brain and identify binding sites for AIV in the neocortex, paleocortex, hippocampus, medial habenula, superior and inferior colliculi, caudate putamen, thalamus, dorsal tegmentum, central gray, red nucleus, inferior olivary, oculomotor and hypoglossal nuclei and cerebellum. Binding of [125I]AIV in selected regions was shown to be of high affinity (Kd = 0.60-1.47 nM), saturable (maximal number of binding sites = 181-449 fmol/mg of protein) and specific. This binding site was shown to be distinct from the AT1 and AT2 sites with Ki values > 10(-4) M for DuP 753, CGP42112A and PD123177. Changes at the N-terminal of the peptide, either by removal of the valine or by extension of the peptide, resulted in a large decrease in binding affinity. In contrast, C-terminal extensions resulted in little change in affinity for the binding site. Guanosine 5'-0-(3-thiotriphosphate) was shown to have no effect on binding, suggesting that the guinea pig brain binding site is not G-protein-linked. Potential functions associated with this newly discovered A binding site are discussed.
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PMID:Central angiotensin IV binding sites: distribution and specificity in guinea pig brain. 837 Nov 70

Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variations in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.
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PMID:Characterization of ATM gene mutations in 66 ataxia telangiectasia families. 988 33

Various AT1 receptor antagonists including losartan are known to inhibit human platelet activation by antagonising TXA2/PGH2 receptors (TP receptors). Presently, we check a hypothesis that losartan, an imidazole derivative in contrast with valsartan, a non-imidazole compound, may inhibit human platelet activation also through inhibition of TXA2 synthesis. Inhibitory action of losartan (2-n butyl-4-chloro-5-hydroxymethyl-1-beta(2'-(1H-tetrazol-5yl)biphenyl-4-yl)methyl] imidazole), its active metabolite EXP 3174 (2-n-butyl-4-chloro-1-beta (2-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl]imidazole-5-carboxylic acid) and valsartan ((S)-N-valeryl-N-(beta2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]valine), on collagen-induced platelet aggregation and TXA2 generation was compared to effects achieved by each compound on U46619-induced aggregation in aspirinized platelets. Losartan and aspirin inhibited collagen-induced platelet aggregation with approximately the same potency, whereas EXP 3174 and valsartan showed much weaker antiplatelet effects. Interestingly, losartan, EXP 3174 and valsartan displayed similar potencies as inhibitors of U46619-induced aggregation in asprinized platelets as in collagen-induced aggregation in non-aspirinized platelets. None of the above three AT1 antagonists, up to a concentration of 300 microM, did influence collagen-induced TXA2 synthesis in human platelets. In conclusion, antiplatelet effects of AT1 antagonists, irrespective of the presence or absence of non-condensed imidazole in their chemical structure, involve antagonism of TP receptors but not inhibition of TXA2 synthesis in platelets.
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PMID:Antiplatelet action of losartan involves TXA2 receptor antagonism but not TXA2 synthase inhibition. 1119 44

The phosphoinositide-dependent kinase PDK1 activates the serum- and glucocorticoid-inducible kinase isoforms SGK1, SGK2, and SGK3 and protein kinase B, which in turn are known to up-regulate a variety of sodium-coupled transporters. The present study was performed to explore the role of PDK1 in amino acid transport. As mice completely lacking functional PDK1 are not viable, mice expressing 10-25% of PDK1 (pdk1(hm)) were compared with their wild-type (WT) littermates (pdk1(wt)). Body weight was significantly less in pdk1(hm) than in pdk1(wt) mice. Despite lower body weight of pdk1(hm) mice, food and water intake were similar in pdk1(hm) and pdk1(wt) mice. According to Ussing chamber experiments, electrogenic transport of phenylalanine, cysteine, glutamine, proline, leucine, and tryptophan was significantly smaller in jejunum of pdk1(hm) mice than in pdk1(wt) mice. Similarly, electrogenic transport of phenylalanine, glutamine, and proline was significantly decreased in isolated perfused proximal tubules of pdk1(hm) mice. The urinary excretion of proline, valine, guanidinoacetate, methionine, phenylalanine, citrulline, glutamine/glutamate, and tryptophan was significantly larger in pdk1(hm) than in pdk1(wt) mice. According to immunoblotting of brush border membrane proteins prepared from kidney, expression of the Na+-dependent neutral amino acid transporter B(0)AT1 (SLC6A19), the glutamate transporter EAAC1/EAAT3 (SLC1A1), and the transporter for cationic amino acids and cystine b(0,+)AT (SLC7A9) was decreased but the Na+/proline cotransporter SIT (SLC6A20) was increased in pdk1(hm) mice. In conclusion, reduction of functional PDK1 leads to impairment of intestinal absorption and renal reabsorption of amino acids. The combined intestinal and renal loss of amino acids may contribute to the growth defect of PDK1-deficient mice.
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PMID:Reduced intestinal and renal amino acid transport in PDK1 hypomorphic mice. 1707 98

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that acts downstream of the phosphatidylinositol 3-kinase signaling pathway and regulates a wide range of cellular functions including transcription, translation, proliferation, apoptosis, and autophagy. Whereas genetic alterations that result in mTOR activation are frequently present in human cancers, whether the mTOR gene itself becomes an oncogene through somatic mutation has remained unclear. We have now identified a somatic non-synonymous mutation of mTOR that results in a leucine-to-valine substitution at amino acid position 2209 in a specimen of large cell neuroendocrine carcinoma. The mTOR(L2209V) mutant manifested marked transforming potential in a focus formation assay with mouse 3T3 fibroblasts, and it induced the phosphorylation of p70 S6 kinase, S6 ribosomal protein, and eukaryotic translation initiation factor 4E-binding protein 1 in these cells. Examination of additional tumor specimens as well as public and in-house databases of cancer genome mutations identified another 28 independent non-synonymous mutations of mTOR in various cancer types, with 12 of these mutations also showing transforming ability. Most of these oncogenic mutations cluster at the interface between the kinase domain and the FAT (FRAP, ATM, TRRAP) domain in the 3-D structure of mTOR. Transforming mTOR mutants were also found to promote 3T3 cell survival, and their oncogenic activity was sensitive to rapamycin. Our data thus show that mTOR acquires transforming activity through genetic changes in cancer, and they suggest that such tumors may be candidates for molecularly targeted therapy with mTOR inhibitors.
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PMID:Transforming somatic mutations of mammalian target of rapamycin kinase in human cancer. 2643 19