Mouse alpha-fetoprotein gene 5' regulatory elements are required for postnatal regulation by raf and Rif

Abstract

The mouse alpha-fetoprotein (AFP) gene is expressed at high levels in the yolk sac and fetal liver and at low levels in the fetal gut. AFP synthesis decreases dramatically shortly after birth to low levels that are maintained in the adult liver and gut. AFP expression can be reactivated in the adult liver upon renewed cell proliferation such as during liver regeneration or in hepatocellular carcinomas. Previously, two unlinked genetic loci that modulate postnatal AFP levels were identified. The raf locus controls, at least in part, basal steady-state AFP mRNA levels in adult liver. Rif influences the extent of AFP mRNA induction during liver regeneration. Transgenic mice were used to examine the role of 5' AFP regulatory regions in raf- and Rif-mediated control. A fragment of the AFP 5' region containing enhancer element I, the repressor, and the promoter was linked to the mouse class I H-2Dd structural gene. We demonstrate that this hybrid AFP-Dd transgene is expressed in the appropriate tissues. In addition, it is postnatally repressed and reactivated during liver regeneration in parallel with the endogenous AFP gene. Therefore, proper transcriptional control does not require the AFP structural gene. Furthermore, the AFP 5' control region is sufficient to confer raf and Rif responsiveness to the linked H-2Dd structural gene, suggesting that raf and Rif act at the level of transcriptional initiation.