The long-term goal of this project is to elucidate the molecular mechanism of liver-specific gene expression. The immediate goal is to determine the mechanism of action of one critical liver-enriched transcription factor, hepatocyte nuclear factor 4a (HNF4a). Found primarily in the liver, kidney, intestine and pancreas, HNF4a is a highly conserved member of the superfamily of ligand-dependent transcription factors (nuclear receptors) that regulates many target genes essential to basic metabolism as well as xenobiotic and drug metabolism. Whereas a ligand has not yet been definitively identified for HNF4a, it has been linked to several human diseases including hemophilia, diabetes, atherosclerosis and cancer via regulation of hepatitis B viral genes and P450 (cyp) genes. HNF4a is also known to be an essential gene in organisms ranging from insect to man and to be essential for the adult liver phenotype. Despite the obvious importance of HNF4a, much remains to be elucidated about its mechanism of action. To address this, the following three Specific Aims will be pursued: 1) Investigation of the role of the unusually large F domain in HNF4a function. While our current results indicate that the F domain plays a role in recruiting co-regulatory molecules, little else is known about the structure or function of this unique domain. We will use a variety of in vivo and in vitro methods to investigate the interaction between the F domain and other regions of HNF4a as well as other proteins; 2) Identification and analysis of HNF4a interacting proteins. Studies will be continued on the interaction between HNF4a and known co-regulators using biochemical and molecular biological techniques. Newly identified interacting proteins will also be investigated; 3) Identification and analysis of HNF4a phosphorylation sites. We will finish mapping the more than 13 phosphorylation sites in HNF4a and elucidate their function in vitro and in vivo in cell-based assays.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053892-05
Application #
6553255
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Serrano, Jose
Project Start
1998-06-16
Project End
2007-05-31
Budget Start
2002-07-15
Budget End
2003-05-31
Support Year
5
Fiscal Year
2002
Total Cost
$352,946
Indirect Cost
Name
University of California Riverside
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
City
Riverside
State
CA
Country
United States
Zip Code
92521
Deol, Poonamjot; Fahrmann, Johannes; Yang, Jun et al. (2017) Omega-6 and omega-3 oxylipins are implicated in soybean oil-induced obesity in mice. Sci Rep 7:12488
Chellappa, Karthikeyani; Deol, Poonamjot; Evans, Jane R et al. (2016) Opposing roles of nuclear receptor HNF4? isoforms in colitis and colitis-associated colon cancer. Elife 5:
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Vuong, Linh M; Chellappa, Karthikeyani; Dhahbi, Joseph M et al. (2015) Differential Effects of Hepatocyte Nuclear Factor 4? Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells. Mol Cell Biol 35:3471-90
Deol, Poonamjot; Evans, Jane R; Dhahbi, Joseph et al. (2015) Soybean Oil Is More Obesogenic and Diabetogenic than Coconut Oil and Fructose in Mouse: Potential Role for the Liver. PLoS One 10:e0132672
Chellappa, Karthikeyani; Jankova, Lucy; Schnabl, Jake M et al. (2012) Src tyrosine kinase phosphorylation of nuclear receptor HNF4? correlates with isoform-specific loss of HNF4? in human colon cancer. Proc Natl Acad Sci U S A 109:2302-7
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Sladek, Frances M (2012) The yin and yang of proliferation and differentiation: cyclin D1 inhibits differentiation factors ChREBP and HNF4?. Cell Cycle 11:3156-7
Chellappa, Karthikeyani; Robertson, Graham R; Sladek, Frances M (2012) HNF4?: a new biomarker in colon cancer? Biomark Med 6:297-300
Bolotin, Eugene; Chellappa, Karthikeyani; Hwang-Verslues, Wendy et al. (2011) Nuclear receptor HNF4? binding sequences are widespread in Alu repeats. BMC Genomics 12:560

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