SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4.
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.
Wang
Jen-Chywan
JC
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615.
Stafford
John M
JM
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615.
Granner
Daryl K
DK
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615.
D001665:Binding Sites; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D005947:Glucose; D051557:Hepatocyte Nuclear Factor 4; D051548:Histone Acetyltransferases; D006706:Homeostasis; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D051557:Hepatocyte Nuclear Factor 4; D051958:Nuclear Receptor Coactivator 2; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1; D005947:Glucose