The Role of HNF4alpha in Cell Proliferation

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DESCRIPTION (provided by applicant): Hepatocyte nuclear factor (HNF) 41, an important nuclear receptor required for the morphology and function of the fetal and adult livers, regulates many liver-specific genes involved in various metabolic processes, blood homeostasis, and epithelium architecture. This highly conserved nuclear receptor has various isoforms that differ in the N-terminal and C- terminal domains. These are generated by the use of two alternative promoters and 3' splicing events. There has been evidence suggesting that these splice variants play different roles in liver development. The P1 isoforms (HNF411/12) are expressed exclusively in lat embryo, postnatal and adult livers while the P2 isoforms (HNF417/18) are expressed only in the fetal liver. How these isoforms regulate the transition from proliferating to differentiating cells is yet to be elucidated. Recently, we have shown that HNF411 upregulates cyclin dependent kinase inhibitor p21, a cell cycle inhibitor; we have also shown that the oncoprotein c-Myc abolishes this activity. Others have shown HNF41 interacts with TCF/LEF which is the downstream of the Wnt/2-catenin pathway. Dysfunction in this pathway is associated with liver and other cancers. Our goal is to decipher the role of HNF41 in cell cycle regulation and to investigate the role of the different HNF41 isoforms in that process. We will incorporate molecular and high throughput technology such as co-immunoprecipitiation (co-IP), cell proliferation assays, expression profiling arrays, and chromatin immunoprecipitation sequencing (ChIP-Seq) techniques in our study. We will use both immortalized cancer cell lines and mouse embryonic stem (mES) cells that we will differentiate into the hepatic lineage. ES cells can proliferate indefinitely, just like cancer cells, but they also can differentiate into any specialized cell type. In short, they mimic normal development. Cancer cell lines, on the other hand, provide a system to examine the pathological consequences of disrupting the delicate proliferation-differentiation balance. These two systems will provide complementary approaches to address the fundamental dichotomy between cell proliferation and cell differentiation in liver development and disease.