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Activins are dimeric growth factors composed of beta-subunits, four of which have been isolated so far. Whereas activin beta(A) and beta(B) are expressed in many tissues, the expression of activin beta(C) and beta(E) is confined to the liver. To date no biological role or activity has been assigned to activins formed from beta(C) or beta(E) subunits (activin C and E). Because activin A (beta(A)beta(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 beta(C), beta(E), or beta(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 beta(C), beta(E), or beta(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.