Linked Life Data

8592518

Source:http://linkedlifedata.com/resource/pubmed/id/8592518

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
1996-4-4
pubmed:abstractText
A series of somatic mutations of the TSH receptor gene have been demonstrated in hyperfunctioning thyroid adenomas. The mutations studied up to now cause constitutive (i.e. TSH-independent) activation of the cAMP-regulatory cascade only. As a follow-up to our original study, we have now completely sequenced exon number 10 of the TSH receptor gene in the same series of toxic adenomas. An activating mutation was found in nine of 11 tumors. In addition to the mutations already described, two isoleucine residues belonging to the first and second extracellular loops of the receptor (Ile486 and Ile568) were found mutated. Two different adenomas were found to harbor a different amino acid substitution at residue 486 (Ile486Phe, Ile486Met). Ile568 was mutated to threonine in one. When studied by transfection in COS-7 cells, all three mutations caused very strong activation of the cAMP-regulatory cascade. In addition, the Ile486Phe and, to a lesser extent, the Ile486Met and Ile568Thr mutants stimulated constitutively the inositol phosphate-diacylglycerol cascade. Our results demonstrate that 1) the first and second extracellular loops contribute to the silencing of the unliganded TSH receptor; 2) the two regulatory cascades normally under TSH control can be constitutively activated by somatic mutations of the receptor; 3) the TSH receptor can be activated by mutation of a large number of residues distributed over the first and second extracellular loops, the third intracellular loop, and the third, sixth, and seventh transmembrane segments; 4) activating mutations of the TSH receptor constitute the major cause of toxic adenomas, accounting for about 80% of the cases.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0888-8809
pubmed:author
pubmed:issnType
Print
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
725-33
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:8592518-Adenoma, pubmed-meshheading:8592518-Amino Acid Sequence, pubmed-meshheading:8592518-Animals, pubmed-meshheading:8592518-Base Sequence, pubmed-meshheading:8592518-Calcium, pubmed-meshheading:8592518-Cell Line, Transformed, pubmed-meshheading:8592518-Cercopithecus aethiops, pubmed-meshheading:8592518-Cyclic AMP, pubmed-meshheading:8592518-Gene Expression Regulation, Neoplastic, pubmed-meshheading:8592518-Graves Disease, pubmed-meshheading:8592518-Hyperthyroidism, pubmed-meshheading:8592518-Inositol Phosphates, pubmed-meshheading:8592518-Models, Molecular, pubmed-meshheading:8592518-Molecular Sequence Data, pubmed-meshheading:8592518-Phosphatidylinositol Diacylglycerol-Lyase, pubmed-meshheading:8592518-Phosphoric Diester Hydrolases, pubmed-meshheading:8592518-Point Mutation, pubmed-meshheading:8592518-Protein Conformation, pubmed-meshheading:8592518-Receptors, Thyrotropin, pubmed-meshheading:8592518-Signal Transduction, pubmed-meshheading:8592518-Thyroid Neoplasms, pubmed-meshheading:8592518-Transfection
pubmed:year
1995
pubmed:articleTitle
Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3',5'-monophosphate and inositol phosphate-Ca2+ cascades.
pubmed:affiliation
Institut de Recherche Interdisciplinaire, Faculty of Medicine, University of Brussels, Belgium.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't