The ying/yang relationship of differentiation versus proliferation is a fundamental tenet in the development of multicellular organisms, as well as the basis for cancer. Transcription factors (TFs), such as nuclear receptors (NRs), regulate the genes responsible for carrying out these cellular processes. HNF4? is a highly conserved member of the NR superfamily of ligand dependent TFs. During the past 20+ years, HNF4? has been well characterized for its role in early development, liver differentiation and an inherited form of diabetes (MODY1). More recently, a role for HNF4? has emerged in the intestine/colon and several links to cancer have been reported. Intriguingly, the role for HNF4? in cancer seems to depend on the particular isoform of HNF4?: there are nine isoforms driven by two alternative promoters, P1 and P2. Here, we propose to follow up on the results from the previous round of funding in which we identified the mechanism responsible for differential regulation of the P1- and P2-driven HNF4? isoforms in human colon cancer. That mechanism involves the oncogene Src tyrosine kinase and is impacted by single nucleotide polymorphisms (SNPs) in the HNF4? gene. We will pursue the following three Specific Aims: 1) Determine the role of the P1- versus P2- HNF4? isoforms in the colon by using mouse models, human culture models and human tissue analysis;2) Determine the role of P2- HNF4? in liver cancer and development by using mouse models and cutting edge """"""""-omic"""""""" approaches to decipher the molecular basis for the differences in the isoforms;and 3) Elucidate the effects of the Src tyrosine kinase pathway on HNF4? using mouse and human models. The proposed experiments will provide invaluable insights not just into the molecular mechanisms of cancer but also into the dichotomy between the differentiation and proliferation and molecular mechanisms of nuclear receptor action. They will generate results that could be of use in the clinic to help properly diagnose and treat liver and colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053892-16
Application #
8719973
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Serrano, Jose
Project Start
1998-06-16
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Anatomy/Cell Biology
Type
Earth Sciences/Resources
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:
Alexander, Stephen Ph; Kelly, Eamonn; Marrion, Neil et al. (2015) The Concise Guide to PHARMACOLOGY 2015/16: Overview. Br J Pharmacol 172:5729-43
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
Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I et al. (2012) The transcription factor encyclopedia. Genome Biol 13:R24
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

Showing the most recent 10 out of 25 publications