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.

Public Health Relevance

While cancer death rates decreased in the U.S between 2004 and 2009, certain cancers remain very prevalent and cause large numbers of deaths. Others cancers have increased rates of incidence and yet the survival rates remain very low. For example, colorectal cancer is the third most deadly cancer in the U.S., claiming >50,000 deaths every year. And, the incidence of liver cancer, which has the second lowest survival rate (~15%), is actually increasing. Major risk factors for liver cancer are viral infections that cause hepatitis (e.g., HBV and HCV) as well as the metabolic syndrome that is associated with obesity and diabetes. Colon cancer is also directly impacted by diet. Obesity and diabetes have increased in the U.S. and worldwide to epidemic proportions with more than 55% of adult Americans classified as obese. This proposal examines the role of a gene, HNF4?, in both colon and liver in normal tissue and cancer. The ultimate goal is a better understanding of how these cancers progress so that we can eventually develop better methods of treating them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053892-15A1
Application #
8599216
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
2013-09-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$377,310
Indirect Cost
$127,310
Name
University of California Riverside
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I et al. (2012) The transcription factor encyclopedia. Genome Biol 13:R24
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
Bolotin, Eugene; Chellappa, Karthikeyani; Hwang-Verslues, Wendy et al. (2011) Nuclear receptor HNF4? binding sequences are widespread in Alu repeats. BMC Genomics 12:560
Sladek, Frances M (2011) What are nuclear receptor ligands? Mol Cell Endocrinol 334:3-13
Hwang-Verslues, Wendy W; Sladek, Frances M (2010) HNF4?--role in drug metabolism and potential drug target? Curr Opin Pharmacol 10:698-705
Xie, Xuefen; Liao, Hailing; Dang, Huaixin et al. (2009) Down-regulation of hepatic HNF4alpha gene expression during hyperinsulinemia via SREBPs. Mol Endocrinol 23:434-43
Hwang-Verslues, Wendy W; Sladek, Frances M (2008) Nuclear receptor hepatocyte nuclear factor 4alpha1 competes with oncoprotein c-Myc for control of the p21/WAF1 promoter. Mol Endocrinol 22:78-90
Yang, Chuhu; Bolotin, Eugene; Jiang, Tao et al. (2007) Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters. Gene 389:52-65
Sun, Kai; Montana, Vedrana; Chellappa, Karthikeyani et al. (2007) Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization. Mol Endocrinol 21:1297-311
Maeda, Yutaka; Hwang-Verslues, Wendy W; Wei, Gang et al. (2006) Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4alpha) gene. Biochem J 400:303-13

Showing the most recent 10 out of 16 publications