Role of Smad and trimeric G protein signaling pathway in liver regeneration

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Activin A induces growth arrest of rat hepatocytes in vitro and in vivo. The α_1-adrenergic agonist, norepinephrine (NE), enhances epidermal growth factor (EGF)-stimulated DNA synthesis and inhibits activin A-induced growth inhibition, but the mechanisms of these actions are unclear. Smad proteins have recently been identified as intracellular signaling mediators of transforming growth factor (TGF) -β family members. In the present study, we explored how NE modulates the Smad signaling pathway in rat cultured hepatocytes. We demonstrate that NE inhibits activin A-induced nuclear accumulation of Smad2/3, and that NE rapidly induces inhibitory Smad7 mRNA expression. Infection of Smad7 adenovirus into rat hepatocytes inhibited activin A-induced nuclear accumulation of Smad2/3, enhanced EGF-stimulated DNA synthesis and abolished the growth inhibitory effect of activin A. We also demonstrated that the induction of Smad7 by NE is dependent on nuclear factor-KB (NF-KB). The amount of active NF-KB complex rapidly increased after NE treatment. Preincubation of the cells with an NF-KB pathway inhibitor N-tosyl-L-phenylalanine chloromethyl ketone abolished the NE-induced Smad7 expression. These results indicate a mechanism of transmodulation between the Smad and trimeric G protein signaling pathways in rat hepatocytes.