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Titolo:
Loss-of-function and dominant-negative mechanisms associated with hepatocyte nuclear factor-1 beta mutations in familial type 2 diabetes mellitus
Autore:
Tomura, H; Nishigori, H; Sho, K; Yamagata, K; Inoue, I; Takeda, J;
Indirizzi:
Gunmabashi, Dept Cell Biol, Inst Mol & Cellular Regulat, Mol Genet Lab, Mae Gunma Univ Maebashi Gumma Japan 3718512 lular Regulat, Mol Genet Lab, Mae Osaka Univ, Sch Med, Dept Internal Med 2, Osaka 5650871, Japan Osaka UnivOsaka Japan 5650871 Dept Internal Med 2, Osaka 5650871, Japan
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 19, volume: 274, anno: 1999,
pagine: 12975 - 12978
SICI:
0021-9258(19990507)274:19<12975:LADMAW>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
HOMEODOMAIN PROTEINS; GLUCOSE-TRANSPORTER; GENE; TRANSCRIPTION; HOMEOPROTEIN; MODY; HETERODIMERS; MEMBER; GLUT2; CELL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Takeda, J Gunma9-15v, Dept Cell Biol, Inst Mol & Cellular Regulat, Mol Genet Lab, 3-3 Gunma Univ 3-39-15 Showa Machi Maebashi Gumma Japan 3718512 3-3
Citazione:
H. Tomura et al., "Loss-of-function and dominant-negative mechanisms associated with hepatocyte nuclear factor-1 beta mutations in familial type 2 diabetes mellitus", J BIOL CHEM, 274(19), 1999, pp. 12975-12978

Abstract

Hepatocyte nuclear factor (HNF)-1 beta, a homeodomain-containing transcription factor, regulates gene expression in a dimerized form in pancreas, liver, and some other tissues. Recent genetic studies have identified two HNF-1 beta mutations, R177X and A263fsinsGG, in subjects with a monogenic form of type 2 diabetes. Despite the defects being in the same gene, diverse severities of disease are observed in the affected subjects. To investigate the molecular mechanism by which mutations might cause various phenotypic features, wild type and mutant proteins were transiently expressed in insulin-producing (MIN6) and hepatic (HepG2) cells. Luciferase reporter assay showed that both mutations resulted in a marked reduction of transactivation activity. Because their dimerization activity was found to be intact by the yeast two-hybrid system, it was possible that they were dominant-negative to wild type activity. When co-expressed with wild type, both of the mutants significantly decreased wild type activity in HepG2 cells. In contrast, although A263fsinsGG functioned similarly in MIN6 cells, R177X failed to affectwild type activity in this cell line. Immunohistochemical analysis of the mutants suggests that this functional divergence might be generated by the modification of nuclear localization. These results suggest that HNF-1 betamutations may impair pancreatic beta-cell function by loss-of-function anddominant-negative mechanisms.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 13/07/20 alle ore 07:16:32