Regulation of Cytochrome P450 Expression by Ras- and β-Catenin-Dependent Signaling

Albert      Braeuning

Abstract

Signaling through the Ha-Ras/ mitogen-activated protein kinase cascade and through the Wnt/ β-catenin signaling pathway has been implicated in various developmental processes as well as in carcinogenesis of different organs by regulating cell growth and differentiation. In particular, both pathways have been reported to play an important role in embryonic liver development as well as in liver regeneration after partial hepatectomy. More recently, there is accumulating evidence for a role of Ras- and β-catenin-dependent signal transduction in the regulation of zone-specific gene expression in healthy adult liver. An antagonistic interplay of both pathways was proposed: β-catenin was established to function as a decisive regulator of ‘perivenous’ gene expression in hepatocytes neighboring branches of the central vein, whereas the Ras pathway was linked to transcription of ‘periportal’ genes. Xenobiotic-metabolizing enzymes constitute one of the largest functionally related groups of zonated genes with predominantly perivenous expression of the most abundant enzymes of xenobiotic metabolism. In this review, the current knowledge regarding the role of Ras and β-catenin signaling in the regulation of expression of xenobiotic-metabolizing enzymes from the cytochrome P450 superfamily will be summarized including both in vitro and in vivo observations.

Keywords: Ha-Ras, MAP kinase, WNT, β-catenin, metabolic zonation, liver, cytochrome P450, liver tumor