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

Research output: Contribution to journal › Journal article › Research › peer-review

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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 journal › Journal article › Research › peer-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., Johansen, A., Maestro, M. A., 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, 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

C2 - 12235114

VL - 110

SP - 827

EP - 833

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -

ID: 38457884