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. The alpha(1)-adrenergic agonist, norepinephrine (NE), enhances epidermal growth factor-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-beta 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 epidermal growth factor-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-kappa B (NF-kappa B). The amount of active NF-kappa B complex rapidly increased after NE treatment. Preincubation of the cells with an NF-kappa B pathway inhibitor N-tosyl-l-phenylalanine chloromethyl ketone or infection of the cells with an adenovirus expressing an I kappa B super-repressor (Ad5I kappa B) 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.
Kanamaru
C
C
Department of Medicine, University of Tokyo School of Medicine, Tokyo 113-8655, Japan.
Yasuda
H
H
Takeda
M
M
Ueda
N
N
Suzuki
J
J
Tsuchida
T
T
Mashima
H
H
Ohnishi
H
H
Fujita
T
T
D028341:Activins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D028322:Inhibin-beta Subunits / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051906:Smad7 Protein; D015534:Trans-Activators / Q000096:biosynthesis* / Q000502:physiology
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D015534:Trans-Activators; C422405:activin A; D028341:Activins; D004815:Epidermal Growth Factor; D028322:Inhibin-beta Subunits; D009638:Norepinephrine