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PMID: 12235114 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function.

The Journal of clinical investigation ·Vol. 110 ·No. 6 ·2002-09-00 ·Pages 827-33

Hansen SK, Párrizas M, Jensen ML, Pruhova S, Ek J, Boj SF, Johansen A, Maestro MA, Rivera F, Eiberg H, Andel M, Lebl J, Pedersen O, Ferrer J, Hansen T

Abstract

Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha. More recent data demonstrates that HNF-4alpha expression is dependent on HNF-1alpha in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1alpha to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4alpha promoter (P1). Here we report that the expression of HNF-4alpha in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1alpha, and consequently in reduced HNF-1alpha-dependent activation. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.

MeSH Terms
Adolescent Adult Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Child Child, Preschool DNA-Binding Proteins/genetics,metabolism Diabetes Mellitus, Type 2/genetics,metabolism Female Genes, Reporter Hepatocyte Nuclear Factor 1 Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 1-beta Hepatocyte Nuclear Factor 4 Humans Infant Islets of Langerhans/physiology Male Mutation Nuclear Proteins/genetics,metabolism Pedigree Phosphoproteins/genetics,metabolism Promoter Regions, Genetic Receptors, Glucocorticoid/genetics,metabolism Transcription Factors/genetics,metabolism Transcription, Genetic
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors DNA-Binding Proteins HNF1A protein, human HNF1B protein, human HNF4A protein, human Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 4 MLX protein, human Nuclear Proteins Phosphoproteins Receptors, Glucocorticoid Tcfl4 protein, mouse Transcription Factors Hepatocyte Nuclear Factor 1 Hepatocyte Nuclear Factor 1-beta
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Hansen Sara K
Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark. [email protected]
Párrizas Marcelina
Jensen Maria L
Pruhova Stepanka
Ek Jakob
Boj Sylvia F
Johansen Anders
Maestro Miguel A
Rivera Francisca
Eiberg Hans
Andel Michal
Lebl Jan
Pedersen Oluf
Ferrer Jorge
Hansen Torben
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI15085
Email
[email protected]
Published
2002-09-00
Pages
827-33
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151122
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI15085 PMC Full Text View journal details
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