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Overexpression of Activin ß_C or Activin ß_E in the Mouse Liver Inhibits Regenerative Deoxyribonucleic Acid Synthesis of Hepatic Cells

Department of Toxicology (M.C., W.R.), Institute for Cancer Research and Neuromuscular Research Department (M.C., W.R.), Institute of Anatomy, University of Vienna, 1090 Vienna, Austria; and Ludwig Boltzmann Institute for Pediatric Endocrinology and Immunology (K.H.), 1090 Vienna, Austria

Address all correspondence and requests for reprints to: Walter Rossmanith, Neuromuscular Research Department, Institute of Anatomy, University of Vienna, Währinger Strasse 13, 1090 Wien, Austria. E-mail: walter.rossmanith{at}univie.ac.at.

Activins are dimeric growth factors composed of ß-subunits, four of which have been isolated so far. Whereas activin ß_A and ß_B are expressed in many tissues, the expression of activin ß_C and ß_E is confined to the liver. To date no biological role or activity has been assigned to activins formed from ß_C or ß_E subunits (activin C and E). Because activin A (ß_Aß_A), among its various functions in other tissues, appears to be a negative regulator of liver growth, we hypothesized a similar role for activin C and E. Using a nonviral gene transfer system we specifically delivered genes encoding activin ß_C, ß_E, or ß_A to the mouse liver. The mRNA analysis and reporter gene coexpression both indicated a reproducible temporal and spatial transgene expression pattern. The effects of activin overexpression were studied in the context of a regenerative proliferation of hepatic cells, a result of the tissue damage associated with the hydrodynamics based gene transfer procedure. Activin ß_C, ß_E, or ß_A expression, all temporarily inhibited regenerative DNA synthesis of hepatocytes and nonparenchymal cells, though to a varying degree. This first report of a biological activity of activin C and E supports an involvement in liver tissue homeostasis and further emphasizes the role of the growing activin family in liver physiology.

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