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Báo cáo khoa học: Serum components and activated Ha-ras antagonize expression of perivenous marker genes stimulated by b-catenin signaling in mouse hepatocytes

Hepatocytes of the periportal and perivenous zones of the liver lobule show marked differences in the contents and activities of many enzymes and other proteins. Previous studies from our and other groups have pointed towards an important role of b-catenin-dependent signaling in the regula-tion of expression of genes encoding proteins with preferential perivenous localization, whereas, in contrast, signaling through Ras-dependent path-way(s) may induce a ‘periportal’ phenotype. | ễFEBS Journal Serum components and activated Ha-ras antagonize expression of perivenous marker genes stimulated by b-catenin signaling in mouse hepatocytes Albert Braeuning1 Moritz Menzel1 Eva-Maria Kleinschnitz1 Naomoto Harada2 Yoshitaka Tamai2 Christoph Kohle1 Albrecht Buchmann1 and Michael Schwarz1 1 Institute of Pharmacology und Toxicology Department of Toxicology University of Tuebingen Germany 2 Transgenic AnimalResearch Tsukuba Research Institute Banyu PharmaceuticalCo. Ltd Ibaraki Japan Keywords b-catenin gene expression Ha-ras liver tumor metabolic zonation Correspondence M. Schwarz Institute of Pharmacology and Toxicology Department of Toxicology University of Tuebingen Wilhelmstr. 56 72074 Tuebingen Germany Fax 49 7071 29 2273 Tel 49 7071 29 77398 E-mail michael.schwarz@uni-tuebingen.de Received 27 March 2007 revised 1 June 2007 accepted 18 July 2007 doi 10.1111 j.1742-4658.2007.06002.x Hepatocytes of the periportal and perivenous zones of the liver lobule show marked differences in the contents and activities of many enzymes and other proteins. Previous studies from our and other groups have pointed towards an important role of b-catenin-dependent signaling in the regulation of expression of genes encoding proteins with preferential perivenous localization whereas in contrast signaling through Ras-dependent path-way s may induce a periportal phenotype. We have now conducted a series of experiments to further investigate this hypothesis. In transgenic mice with scattered expression of an activated Ha-ras Ha-rasG12V mutant in liver expression of the perivenous markers glutamine synthetase and two cytochrome P450 isoforms was completely abolished in those hepatocytes demonstrating constitutively activated extracellular signal-regulated kinase activity even though they were located directly adjacent to central veins. Similarly incubation of primary hepatocytes or hepatoma cells with increasing amounts of serum caused a concentration-dependent attenuation of