Smad7 is induced by norepinephrine and protects rat hepatocytes from activin A-induced growth inhibition

Activin A induces growth arrest of rat hepatocytes in vitro and in vivo. Th e alpha (1)-adrenergic agonist, norepinephrine (NE), enhances epidermal gro wth factor-stimulated DNA synthesis and inhibits activin A-induced growth i nhibition, but the mechanisms of these actions are unclear. Smad proteins h ave recently been identified as intracellular signaling mediators of transf orming growth factor-beta family members. In the present study, we explored how NE modulates the Smad signaling pathway in rat cultured hepatocytes. W e demonstrate that NE inhibits activin A-induced nuclear accumulation of Sm ad2/3 and that NE rapidly induces inhibitory Smad7 mRNA expression. Infecti on of Smad7 adenovirus into rat hepatocytes inhibited activin A-induced nuc lear accumulation of Smad2/3, enhanced epidermal growth factor-stimulated D NA synthesis, and abolished the growth inhibitory effect of activin A. We a lso demonstrated that the induction of Smad7 by NE is dependent on nuclear factor-kappaB (NF-kappaB). The amount of active NF-kappaB complex rapidly i ncreased after NE treatment. Preincubation of the cells with an NF-kappaB p athway inhibitor N-tosyl-L-phenylalanine chloromethyl ketone or infection o f the cells with an adenovirus expressing an I kappaB super-repressor (Ad5I kappaB) abolished the NE-induced Smad7 expression. These results indicate a mechanism of transmodulation between the Smad and trimeric G protein sign aling pathways in rat hepatocytes.