Hepatocyte Nuclear Factor-4alpha1 (HNF4α1) is essential in liver development and maintenance of the differentiated liver phenotype. Here, we demonstrated that, in response to cellular stress, p53 down-regulates expression of the human HNF4α gene via the proximal P1 promoter. The mechanism by which p53 down regulates the P1 promoter appears to be multifaceted and involves recruitment of HDAC activity to the P1 promoter and antagonism of the transactivation ability of HNF6a, a positive regulator of the P1 promoter, by p53.

I also found that HNF4α1 plays a role in cell cycle regulation and restrains cell proliferation in part by activating expression of the cyclin dependent kinase inhibitor p21/WAF1 (CDKN1A). HNF4α1 activates the expression of p21 primarily by interacting with Sp1 on the p21 promoter. Direct DNA binding by HNF4α1 is not necessary for p21 promoter activation. Moreover, we identified a new HNF4α 1 target gene, nerve injury induced protein 1 (Ninjurin1, NINJ1), a novel cell adhesion protein associated with activation of p21 expression, cell cycle arrest, and cell senescence in liver tissues. This finding provides an alternative, indirect mechanism by which HNF4α1 may activate p21 expression.

Competition between HNF4α1 and oncoprotein c-Myc for regulation of the p21 promoter was also observed. In this competition, c-Myc may displace HNF4α1 from Sp1 bound to the p21 promoter, sequester HNF4α1 in solution, and/or block the ability of HNF4α1 on the promoter to activate p21 expression. We also showed that c-Myc competes with HNF4α1 for control of apolipoprotein CIII (APOC3), a gene associated with the differentiated hepatic phenotype. These results suggest a potential role for HNF4α1 in liver regeneration and hepatocellular carcinoma (HCC) progression as well as a general mechanism by which HNF4α1 and c-Myc compete for control of gene expression that may underly the dichotomy between cellular differentiation and proliferation, a fundamental aspect of both normal development and tumor progression.