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Smad7 dependent expression signature highlights BMP2 and HK2 signaling in HSC transdifferentiation
Bernd Denecke, Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University, 52074 Aachen, Germany
Lucia Wickert, Institute of Clinical Chemistry and Pathobiochemistry of RWTH-University Hospital, 52074 Aachen, Germany
Yan Liu, Steven Dooley, Nadja M Meindl-Beinker, Molecular Hepatology, Alcohol Induced Diseases, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
Loredana Ciuclan, Department of Biology, Babes-Bolyai University, 400084 Cluj-Napoca, Romania
Author contributions: Denecke B, Wickert L and Liu Y performed the majority of the experiments and were involved in editing the manuscript and preparing the figures; Ciuclan L was directly involved in discussing the results and editing the manuscript; Dooley S was involved in designing the study and providing financial support for this work; Meindl-Beinker NM was involved in designing and coordinating the study and writing the manuscript.
Supported by Deutsche Forschungsgemeinschaft DO373/6-1 and SFB TRR77, BMBF (HepatoSys), European Research Advisory Board and the Schlieben-Lange-Programm of the Ministerium für Wissenschaft, Forschung und Kunst of Baden-Württemberg and the Europäische Sozialfond
Correspondence to: Dr. Nadja M Meindl-Beinker, Molecular Hepatology, Alcohol Induced Diseases, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. firstname.lastname@example.org
Telephone: +49-621-3834983 Fax: +49-621-3831467
Received: April 14, 2010
Revised: May 11, 2010
Accepted: May 18, 2010
Published online: November 7, 2010
AIM: To analyse the influence of Smad7, antagonist of transforming growth factor (TGF)-β canonical signaling pathways on hepatic stellate cell (HSC) transdifferentiation in detail.
METHODS: We systematically analysed genes regulated by TGF-β/Smad7 in activated HSCs by microarray analysis and validated the results using real time polymerase chain reaction and Western blotting analysis.
RESULTS: We identified 100 known and unknown targets underlying the regulation of Smad7 expression and delineated 8 gene ontology groups. Hk2, involved in glycolysis, was one of the most downregulated proteins, while BMP2, activator of the Smad1/5/8 pathway, was extremely upregulated by Smad7. However, BMP2 dependent Smad1 activation could be inhibited in vitro by Smad7 overexpression in HSCs.
CONCLUSION: We conclude (1) the existence of a tight crosstalk of TGF-β and BMP2 pathways in HSCs and (2) a Smad7 dependently decreased sugar metabolism ameliorates HSC activation probably by energy withdrawal.