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Activin Signal Transduction in Cell Growth, Differentiation and Apoptosis

细胞生长、分化和凋亡中的激活素信号转导

基本信息

批准号：
08458199
负责人：
SUGINO Hiromu
金额：
$ 4.22万
依托单位：
University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Activin belonging to the TGF-beta superfamily binds to and signals through a receptor complex comprising two transmembrane serine/threonine kinases, called type I and type II.So far, two type II (ActR-IIA,-IIB) and two type I (ActR-IA,IB) activin receptors have been cloned from mammalian sources. In this study, we attempted to elucidate the role of type I receptors in activin signaling for growth, differentiation and apoptosis, and obtained following results.(1) We established stable HS-72 transfectants overexpressing ActR-IA or ActR-IB by the electroporation procedure. Overexpression of ActR-IA suppressed activin-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that overexpressed ACtR-IB significantly facilitated activin induced apoptosis. These results indicate that ActR-IA and ActR-IB are distinct from each other in activin signal transduction.(2) Significant degradation of a cytoskeleton, alpha-fodrin was observed upon activin-induced apoptosis in HS-72 cells. Overexpression of ActR-IA in HS-72 cells caused prevention of the alpha-fodrin degradation, suggesting that the apoptotic signal of activin in relevant to the proteolytic degradation of alpha-fodrin.(3) Follistatin (activin-binding protein) was found to promote the binding of activin to cell surface heparan sulfate. When the cells were incubated with ^<125>I-activin in the presence of follistatin, significant degradation of activin was observed. This activin degradation was abolished by heparan sulfate, chloroquine, and lysosomal protease inhibitors. These results indicate that cell-associated follistatin accelerates the uptake of activin into cells, leading to increased degradation by lysosomal enzymes, and thus plays a role in the activin clearance system.

激活素属于tgf - β超家族，通过由两种跨膜丝氨酸/苏氨酸激酶（称为I型和II型）组成的受体复合物结合并发出信号。迄今为止，已从哺乳动物中克隆出2个II型（acr - iia,-IIB）和2个I型（acr - ia，IB）激活素受体。在本研究中，我们试图阐明I型受体在激活素信号传导中对生长、分化和凋亡的作用，得到了以下结果。(1)通过电穿孔法建立了稳定的过表达acr - ia或acr - ib的HS-72转染物。ActR-IA的过表达抑制激活素诱导的G1期细胞周期阻滞，这是通过诱导p21（一种周期蛋白依赖的激酶抑制剂）抑制视网膜母细胞瘤蛋白磷酸化和随后的细胞凋亡引起的。相比之下，过表达ACtR-IB的HS-72克隆显著促进了激活素诱导的细胞凋亡。这些结果表明acr - ia和acr - ib在激活信号转导方面存在差异。(2)激活素诱导HS-72细胞凋亡后，细胞骨架α -fodrin明显降解。在HS-72细胞中过表达acr - ia可阻止α -fodrin的降解，提示激活素的凋亡信号与α -fodrin的蛋白水解降解有关。(3) Follistatin（激活素结合蛋白）可促进激活素与细胞表面硫酸肝素的结合。当细胞在卵泡抑素存在的情况下与^<125>I-activin孵育时，观察到激活素的明显降解。这种激活素降解被硫酸肝素、氯喹和溶酶体蛋白酶抑制剂所消除。这些结果表明，细胞相关的卵泡抑素加速激活素进入细胞的摄取，导致溶酶体酶的降解增加，从而在激活素清除系统中发挥作用。