Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4α

被引：25

作者：

Hertz, R

Ben-Haim, N

Petrescu, AD

Kalderon, B

Berman, I

Eldad, N

Schroeder, F

Bar-Tana, J ^{[1
]}

机构：

[1] Hebrew Univ Jerusalem, Sch Med, Dept Human Nutr & Metab, IL-91120 Jerusalem, Israel

[2] Texas A&M Univ, Dept Physiol & Pharmacol, College Stn, TX 77843 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2003年 / 278卷 / 25期

关键词：

D O I：

10.1074/jbc.M212138200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4alpha result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4alpha fail to transactivate transcription of HNF-4alpha-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4alpha. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4alpha, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4alpha. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4alpha agonist nutrients and drugs.

引用

收藏

页码：22578 / 22585

页数：8

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