Developing a Model of AFP Transcriptional Regulation by Afr2, a Gene Implicated in Liver Cancer

Abstract

alphafetoprotein (AFP) is a protein that is active during liver development and hepatocellular differentiation that is under the transcriptional control of two regulators – Afr1 and Afr2. Afr2 acts to transcriptionally reactivate AFP in liver regeneration and tumorigenesis. This observation led to AFP utilization as a diagnostic marker for hepatocarcinogenesis. The purpose of this study was to identify and clone Afr2 candidate genes. To begin, the AFP promoter was analyzed for potential transcription factors. A genetic map of chromosome 2 was corrected and utilized to localize the candidate region more accurately. This region was analyzed for genes variant between two mouse strains (C3H/HeJ and C57BL/6) with opposite AFP reactivation phenotypes. Candidate genes were also identified from gene expression analyses from the same strains. These variant genes were then analyzed for interactions with potential AFP transcription factors and others within the candidate pool. This identified a candidate pathway containing Ciao1, WT1, and Ywhae.