S6K1- and βTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth
S6K1- and βTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth
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DOI：
10.1126/science.1130276
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发表时间：
2006-10-20
期刊：
影响因子：
56.9
通讯作者：
Pagano, Michele
中科院分区：
文献类型：
--
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
肿瘤抑制因子程序性细胞死亡蛋白4（PDCD4）抑制翻译起始因子eIF4A，eIF4A是一种RNA解旋酶，催化信使RNA（mRNA）5'非翻译区（5'UTR）二级结构的解旋。作为对有丝分裂原的响应，PDCD4在Ser（67）上被蛋白激酶S6K1快速磷酸化，随后通过泛素连接酶SCF β TRCP降解。在培养的细胞中，不能结合β TRCP的稳定的PDCD4突变体的表达抑制了具有结构化5' UTR的mRNA的翻译，导致细胞尺寸变小，并减缓了细胞周期进程。我们建议，调节降解PDCD4在有丝分裂原的反应，允许有效的蛋白质合成，从而细胞生长。
The tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase that catalyzes the unwinding of secondary structure at the 5' untranslated region (5'UTR) of messenger RNAs (mRNAs). In response to mitogens, PDCD4 was rapidly phosphorylated on Ser(67) by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase SCF beta TRCP. Expression in cultured cells of a stable PDCD4 mutant that is unable to bind beta TRCP inhibited translation of an mRNA with a structured 5' UTR, resulted in smaller cell size, and slowed down cell cycle progression. We propose that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth.