Intracellular signals of activin-A mediating growtharrest and apoptosis

激活素反应是通过激活素与一对特定的受体结合而启动的，称为激活素I型受体(ACTR-I)和激活素II型受体(ACTR-II)，导致ACTR-I的激活，信号通过受体-激酶介导的Smads的磷酸化传递到Smad2/3。磷酸化的Smad2/3与Smad4形成异源低聚物，转位到细胞核，反式激活执行激活素作用的基因。抑制性Smad如Smad6和Smad7可以抑制TGFfbeta的生物学活性。在本研究中，我们利用HS-72小鼠杂交瘤细胞研究了激活素-A诱导生长停滞和凋亡的分子机制。1)激活素信号通过ACTR-IB而不是ACTR-I介导，而ACTR-I的过表达抑制了ACTR-JB介导的激活素效应。2)激活素诱导的生长停滞和细胞凋亡均由Smad2的磷酸化介导。2)激活素-A通过激活p21CIP1/WAF1的表达而诱导生长停滞。4)Smad7是激活素诱导的基因产物，通过抑制Smad2的磷酸化负调控激活素诱导的生长停滞和凋亡。

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.