Intracellular signals of activin-A mediating growtharrest and apoptosis

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Activin response is initiated by the binding of activin to a pair of specific receptors, designated as activin type I receptor (ActR-I) and activin type II receptor (ActR-II), leading to activation of ActR-I.The signal is transferred to Smad2/3 through the receptor-kinase mediated phosphorylation of Smads. The phosphorylated Smad2/3 form hetero-oligomers with Smad4, translocate to the nucleus and transactivate genes executing activin effects. Inhibitory Smads such as Smad6 and Smad7 has been reported to inhibit biological activities of TGFfbeta.In this research project, we investigated the molecular mechanisms by which activin-A induced growth arrest and apoptosis using HS-72 mouse hybridoma cells. The followings are new findings obtained by this study :1) Activin-signals for growth arrest and apoptosis were mediated through ActR-IB but not ActR-I and overexpression of ActR-I inhibited these activin-effects mediated through ActR-JB.2) Both activin-induced growth arrest and apoptosis were mediated by phosphorylation of Smad2.3) Activin-A induced growth arrest by activating p2lCIPl/WAF1 expression.4) Smad7 was an activin-inducible gene product and negatively regulated activin-induced growth arrest and apoptosis by inhibiting Smad2 phosphorylation.