Glycogen synthase kinase-3β positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1
Glycogen synthase kinase-3β positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1
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DOI：
10.1038/onc.2013.113
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发表时间：
2014-03-27
期刊：
影响因子：
8
通讯作者：
Yoon, S-O
中科院分区：
文献类型：
--
作者：
Shin, S.;Wolgamott, L.;Yoon, S-O
蛋白质合成在控制细胞增殖中起着关键作用，它的失控与病理条件有关，尤其是癌症。雷帕霉素是一种哺乳动物靶向雷帕霉素复合体1(MTORC1)的抑制剂，已知可抑制蛋白质合成。然而，在许多癌症类型中，它并不能实质性地抑制蛋白质合成和细胞增殖。我们对寻找雷帕霉素耐药癌症的新靶点很感兴趣。翻译的限速因子是真核细胞翻译起始因子4E(EIF4E)，它受eIF4E结合蛋白1(4E-BP1)的负调控。在此，我们提供了糖原合成酶激酶(GSK)-3β通过正向调节蛋白质合成促进细胞增殖的证据。我们发现GSK-3β使4E-BP1磷酸化并失活，从而增加eIF4E依赖的蛋白质合成。考虑到调节蛋白质合成途径的临床相关性，我们的研究为癌症治疗提供了一个有前景的新策略和靶点。
Protein synthesis has a key role in the control of cell proliferation, and its deregulation is associated with pathological conditions, notably cancer. Rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), was known to inhibit protein synthesis. However, it does not substantially inhibit protein synthesis and cell proliferation in many cancer types. We were interested in finding a novel target in rapamycin-resistant cancer. The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). Here, we provide evidence that glycogen synthase kinase (GSK)-3 beta promotes cell proliferation through positive regulation of protein synthesis. We found that GSK-3 beta phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis. Considering the clinical relevance of pathways regulating protein synthesis, our study provides a promising new strategy and target for cancer therapy.