Faculty Collaboration Database

Regulation of a transcription factor network required for differentiation and metabolism. Science 1998 Jul 31;281(5377):692-5

Date

07/31/1998

Pubmed ID

9685261

DOI

10.1126/science.281.5377.692

Scopus ID

2-s2.0-0032584567 (requires institutional sign-in at Scopus site)   305 Citations

Abstract

Hepatocyte nuclear factors (HNFs) are a heterogeneous class of evolutionarily conserved transcription factors that are required for cellular differentiation and metabolism. Mutations in HNF-1alphaand HNF-4alpha genes impair insulin secretion and cause type 2 diabetes. Regulation of HNF-4/HNF-1 expression by HNF-3alpha and HNF-3beta was studied in embryoid bodies in which one or both HNF-3alpha or HNF-3beta alleles were inactivated. HNF-3beta positively regulated the expression of HNF-4alpha/HNF-1alpha and their downstream targets, implicating a role in diabetes. HNF-3beta was also necessary for expression of HNF-3alpha. In contrast, HNF-3alpha acts as a negative regulator of HNF-4alpha/HNF-1alpha demonstrating that HNF-3alpha and HNF-3beta have antagonistic transcriptional regulatory functions in vivo. HNF-3alpha does not appear to act as a classic biochemical repressor but rather exerts its negative effect by competing for HNF-3 binding sites with the more efficient activator HNF-3beta. In addition, the HNF-3alpha/HNF-3beta ratio is modulated by the presence of insulin, providing evidence that the HNF network may have important roles in mediating the action of insulin.

Author List

Duncan SA, Navas MA, Dufort D, Rossant J, Stoffel M

MESH terms used to index this publication - Major topics in bold

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cell Differentiation
Clone Cells
DNA-Binding Proteins
Diabetes Mellitus, Type 2
Embryonic and Fetal Development
Endoderm
Gene Expression Regulation
Gene Expression Regulation, Developmental
Gene Targeting
Glucose
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-alpha
Hepatocyte Nuclear Factor 1-beta
Hepatocyte Nuclear Factor 3-alpha
Hepatocyte Nuclear Factor 3-beta
Hepatocyte Nuclear Factor 4
Insulin
Mice
Mutation
Nuclear Proteins
Phenotype
Phosphoproteins
Stem Cells
Transcription Factors
Up-Regulation