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

TY - JOUR

T1 - Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function

AU - Hansen, Sara K

AU - Párrizas, Marcelina

AU - Jensen, Maria L

AU - Pruhova, Stepanka

AU - Ek, Jakob

AU - Boj, Sylvia F

AU - Johansen, Anders

AU - Maestro, Miguel A

AU - Rivera, Francisca

AU - Eiberg, Hans

AU - Andel, Michal

AU - Lebl, Jan

AU - Pedersen, Oluf

AU - Ferrer, Jorge

AU - Hansen, Torben

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Animals

KW - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors

KW - Child

KW - Child, Preschool

KW - DNA-Binding Proteins

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Genes, Reporter

KW - Hepatocyte Nuclear Factor 1

KW - Hepatocyte Nuclear Factor 1-alpha

KW - Hepatocyte Nuclear Factor 1-beta

KW - Hepatocyte Nuclear Factor 4

KW - Humans

KW - Infant

KW - Islets of Langerhans

KW - Male

KW - Mutation

KW - Nuclear Proteins

KW - Pedigree

KW - Phosphoproteins

KW - Promoter Regions, Genetic

KW - Receptors, Glucocorticoid

KW - Transcription Factors

KW - Transcription, Genetic

U2 - 10.1172/JCI15085

DO - 10.1172/JCI15085

M3 - Journal article

C2 - 12235114

SN - 0021-9738

VL - 110

SP - 827

EP - 833

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 6

ER -