The Biological Function Of The Nuclear Receptor Lrh-1 Cofactor Prox1

Nuclear receptor liver receptor homolog-1 (also known as Lepepepepepepepepominated as NR5A2) is a member of the FTZ-F1 subfamily of nuclear receptor superfamily. Accumulating data on the biological function of LRH-1 has shown in recent years that it plays important roles in regulating the expression of a number of cellular and viral genes which are actively involved in a wide range of biological processes such as the bile acid biosynthesis, liver specific gene regulatory network and hepatitis B virus replication. It was revealed that LRH-1 has emerged as an essential regulator for the expression of cyp7a1 which encodes the rate-limiting enzyme in bile acid synthesis. To further analysis the molecule mechanism of LRH-1 transactivation, we investigate the research of hLRH-1 cofactor. Chapter One: Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-α-hydroxylase gene. In this report, we demonstrate Prox1, a prospero-related homeobox transcription factor, identified through a yeast two hybrid screening, can directly interact with human LRH-1 (hLRH-1) and suppresses hLRH-1-mediated transcriptional activation of human cyp7a1 gene. Furthermore, we elaborately define the interaction regions between these two proteins. Report analysis demonstrates that the suppression by Prox1 on the transcriptional activity of hLRH-1 can be mediated through its interaction with the LBD or the DBD of hLRH-1. Gel shift assays reveal that Prox1 impairs the binding of hLRH-1 to the promoter of human cyp7a1 gene. Our finding could promote the study of its transcriptional regulation, and as well facilitate portraying the physiological roles of LRH-1 in the process of various complicated physiological pathways. Besides, it could elucidate that Prox1 is involved in bile acid metabolism in vivo.