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J Biol Chem, Vol. 273, Issue 47, 30847-30850, November 20, 1998
From the Department of Molecular Physiology and Biophysics,
Vanderbilt University Medical Center,
Nashville, Tennessee 37232-0615
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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J.-C. Wang, M. Waltner-Law, K. Yamada, H. Osawa, S. Stifani, and D. K. Granner Transducin-like Enhancer of Split Proteins, the Human Homologs of Drosophila Groucho, Interact with Hepatic Nuclear Factor 3beta J. Biol. Chem., June 9, 2000; 275(24): 18418 - 18423. [Abstract] [Full Text] [PDF]
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N. Nasrin, S. Ogg, C. M. Cahill, W. Biggs, S. Nui, J. Dore, D. Calvo, Y. Shi, G. Ruvkun, and M. C. Alexander-Bridges DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells PNAS, September 12, 2000; 97(19): 10412 - 10417. [Abstract] [Full Text] [PDF]
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