Publication Date:
1998-07-31
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duncan, S A -- Navas, M A -- Dufort, D -- Rossant, J -- Stoffel, M -- New York, N.Y. -- Science. 1998 Jul 31;281(5377):692-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratories of Molecular Cell Biology and Metabolic Diseases, Rockefeller University, New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9685261" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
;
Cell Differentiation
;
Clone Cells
;
DNA-Binding Proteins/genetics/*metabolism
;
Diabetes Mellitus, Type 2/genetics/metabolism
;
Embryonic and Fetal Development
;
Endoderm/cytology/*metabolism
;
*Gene Expression Regulation
;
*Gene Expression Regulation, Developmental
;
Gene Targeting
;
Glucose/metabolism
;
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/pharmacology
;
Mice
;
Mutation
;
Nuclear Proteins/genetics/*metabolism
;
Phenotype
;
Phosphoproteins/genetics
;
Stem Cells
;
Transcription Factors/genetics/*metabolism
;
Up-Regulation
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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