SRC-1 and GRIP1 Coactivate Transcription with Hepatocyte Nuclear Factor 4

Wang, Jen-Chywan; Stafford, John M.; Granner, Daryl K.

doi:10.1074/jbc.273.47.30847

Cited by 147Genomics and Chromatin DynamicsEstrogen and related hormone effectsMetabolism, Diabetes, and Cancer

SRC-1 and GRIP1 Coactivate Transcription with Hepatocyte Nuclear Factor 4

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Wang, Jen-Chywan, Stafford, John M., Granner, Daryl K.·1998·Journal of Biological Chemistry

DOI 10.1074/jbc.273.47.30847PMC PMC3968904

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Abstract

Hepatocyte nuclear factor-4 (HNF4), a member of the nuclear receptor superfamily, plays an important role in tissue-specific gene expression, including genes involved in hepatic glucose metabolism. In this study, we show that SRC-1 and GRIP1, which act as coactivators for various nuclear receptors, associate with HNF4 in vivo and enhance its transactivation potential. The AF-2 domain of HNF4 is required for this interaction and for the potentiation of transcriptional activity by these coactivators. p300 can also serve as a coactivator with HNF4, and it synergizes with SRC-1 to further augment the activity of HNF4. HNF4 is also a key regulator of the expression of hepatocyte nuclear factor-1 (HNF1). The overexpression of SRC-1 or GRIP1 enhances expression from a HNF1 gene promoter-reporter in HepG2 hepatoma cells, and this requires an intact HNF4-binding site in the HNF1 gene promoter. Type 1 maturity onset diabetes of young (MODY), which is characterized by abnormal glucose-mediated insulin secretion, is caused by mutations of the HNF4 gene. A mutation of the HNF4-binding site in the HNF1 gene promoter has also been associated with MODY. Thus, HNF4 is involved in the regulation of glucose homeostasis at several levels and along with the SRC-1, GRIP1, and p300 may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus.

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HNF4A was previously shown to recruit several coactivators such as glucocorticoid receptor interacting protein 1, steroid receptor coactivator1 and cAMP response element binding proteins to regulate gene expression.
“In addition to FOXA family members, HNF4A was previously shown to recruit several coactivators such as glucocorticoid receptor interacting protein 1, steroid receptor coactivator1 and cAMP response element binding proteins to regulate gene expression (41, 43).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [43]

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Authors: Wang, J.-C., Stafford, J. M., & Granner, D. K.
Affiliations: Vanderbilt University Medical Center (US)
Corresponding author: Granner, Daryl K.
ORCID: Wang, Jen-Chywan
Stafford, John M.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1998-11
Volume: 273
Issue: 47
Pages: 30847-30850
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.273.47.30847
PMC: PMC3968904
OpenAlex: W2082605633
Cited by: 147
References: 42
Citations by year: 2026: 1 · 2025: 1 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 6 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 7 · 2014: 1 · 2013: 1 · 2012: 5
FWCI: 3.15
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8004 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Vanderbilt University
National Institutes of Health (DK 20593)
Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center
National Institute of General Medical Sciences (GM 07347, T32GM007347)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK035107, DK 20593, DK 25107, R37DK035107, P30DK020593)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: HNF4, SRC-1, GRIP1, P300, transcriptional coactivator, nuclear receptor transactivation, AF-2 domain, HNF1, maturity-onset diabetes of the young, glucose homeostasis, hepatic gene expression, insulin secretion
MeSH terms: Binding Sites, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Glucose, Homeostasis, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Recombinant Fusion Proteins, Transcription Factors, Transcriptional Activation, Saccharomyces cerevisiae Proteins, Histone Acetyltransferases, Hepatocyte Nuclear Factor 4, Nuclear Receptor Coactivator 2, Nuclear Receptor Coactivator 1

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SRC-1 and GRIP1 Coactivate Transcription with Hepatocyte Nuclear Factor 4

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