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

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Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. / Hansen, Sara K; 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.

In: Journal of Clinical Investigation, Vol. 110, No. 6, 2002, p. 827-33.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

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 2002, 'Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function', Journal of Clinical Investigation, vol. 110, no. 6, pp. 827-33. https://doi.org/10.1172/JCI15085

APA

Hansen, S. K., Párrizas, M., Jensen, M. L., Pruhova, S., Ek, J., Boj, S. F., ... Hansen, T. (2002). Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. Journal of Clinical Investigation, 110(6), 827-33. https://doi.org/10.1172/JCI15085

Vancouver

Hansen SK, Párrizas M, Jensen ML, Pruhova S, Ek J, Boj SF et al. Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. Journal of Clinical Investigation. 2002;110(6):827-33. https://doi.org/10.1172/JCI15085

Author

Hansen, Sara K ; 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. / Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. In: Journal of Clinical Investigation. 2002 ; Vol. 110, No. 6. pp. 827-33.

Bibtex

@article{8db8a716cfb547bfa52b738c49f42a6d,
title = "Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function",
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.",
keywords = "Adolescent, Adult, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Child, Child, Preschool, DNA-Binding Proteins, Diabetes Mellitus, Type 2, 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, Male, Mutation, Nuclear Proteins, Pedigree, Phosphoproteins, Promoter Regions, Genetic, Receptors, Glucocorticoid, Transcription Factors, Transcription, Genetic",
author = "Hansen, {Sara K} and Marcelina P{\'a}rrizas and Jensen, {Maria L} and Stepanka Pruhova and Jakob Ek and Boj, {Sylvia F} and Anders Johansen and Maestro, {Miguel A} and Francisca Rivera and Hans Eiberg and Michal Andel and Jan Lebl and Oluf Pedersen and Jorge Ferrer and Torben Hansen",
year = "2002",
doi = "10.1172/JCI15085",
language = "English",
volume = "110",
pages = "827--33",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "6",

}

RIS

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

VL - 110

SP - 827

EP - 833

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -

ID: 38457884