beta-Catenin and Ha-ras - Master Regulators of Zonal Gene Expression in Mouse Liver?

Albert Braeuning

ISBN 978-3-8325-2004-5
129 pages, year of publication: 2008
price: 34.50 €
beta-Catenin and Ha-ras - Master Regulators of Zonal Gene Expression in Mouse Liver?

Hepatocytes located in the periportal or perivenous regions of the liver lobule have different, often complementary functions, as indicated by differences in the content and activity of various enzymes of the intermediary and xenobiotic metabolism. The signaling molecules mediating this metabolic zonation, however, are largely unknown. Based on the correlation of marker protein expression between perivenous hepatocytes and Ctnnb1 (encoding beta-catenin)-mutated mouse hepatomas and between periportal hepatocytes and Ha-ras-mutated hepatomas, a hypothesis was developed postulating that two opposing signals, a Wnt-signal maybe delivered by endothelial cells of the central veins activating a beta-catenin-dependent pathway, and a second signal delivered by blood-borne molecules activating Ras-dependent downstream cascades, regulate gene expression in hepatocytes from the periportal and perivenous domains of the liver lobule.

The impact of beta-catenin and Ras signaling on zonal gene expression was analyzed in vivo by use of different transgenic mouse strains. Zone-specific physiological activation and antagonism of the two pathways were demonstrated. Transcriptome profiles of Ctnnb1- and Ha-ras-mutated tumors closely resembled those of perivenous and periportal hepatocytes. In vitro experiments with primary hepatocytes and hepatoma cells confirmed the role of beta-catenin signaling in the induction of ‘perivenous’ gene expression, particularly of drug-metabolizing enzymes. Inducibility of drug-metabolizing enzymes by xenobiotics was demonstrated to be modulated by beta-catenin in vitro and in vivo. beta-catenin thereby activated transcription by both direct beta-catenin/ TCF-dependent and indirect mechanisms.

Serum components were shown to inhibit beta-catenin-mediated transcription and to induce the expression of ‘periportal’ markers. Serum-mediated inhibition of betacatenin signaling was not exclusively linked to Ras activation, but also to the action of different ligand-activated nuclear receptors, thus suggesting a complex interplay of different blood-borne molecules in the periportal repression of betacatenin signaling.

In summary, the results favor the hypothesis that gene expression patterns in periportal and perivenous hepatocytes are regulated, at least in part, by Ras- and betacatenin-dependent signaling pathways. In the perivenous areas of the liver lobule, betacatenin seems to act as a master regulator of both basal and inducible expression of enzymes involved in the metabolism of drugs and xenobiotics.