Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs
Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs
复制标题
DOI：
10.1073/pnas.1420671112
复制
发表时间：
2015-04-28
影响因子：
11.1
通讯作者：
Koromilas, Antonis E.
中科院分区：
文献类型：
--
作者：
Wang, Shuo;Patsis, Christos;Koromilas, Antonis E.
转录1的信号换能器和激活器（Stat1）通过免疫调节和细胞自主途径发挥肿瘤抑制作用。在此，我们报告了一种以前未被发现的细胞自主Stat1功能，即它能够通过促进编码细胞周期蛋白依赖性激酶抑制剂p27（Kip1）和抗凋亡蛋白x -连锁凋亡和b细胞淋巴瘤抑制剂xl的mrna的翻译，显示出抗增殖和促进生存的特性。选定mrna的翻译需要Stat1的转录功能，导致IB类PI3K p110 γ亚基上调，翻译抑制因子翻译起始因子4E （eIF4E）结合蛋白1 （4EBP1）表达增加。PI3K γ信号的增加促进了eIF4A抑制剂程序性细胞死亡蛋白4的降解，这有利于在上调eif4e结合蛋白1普遍抑制蛋白质合成的情况下，选择mrna进行帽无关翻译。因此，Stat1抑制细胞增殖，但也使细胞对PI3K药理抑制剂和/或哺乳动物雷帕霉素靶点的抗增殖作用越来越有抵抗力。在培养小鼠和免疫缺陷小鼠中，Stat1也保护ras转化细胞免受阿霉素的基因毒性作用。我们的研究结果表明mRNA翻译在细胞自主Stat1功能中发挥重要作用，对肿瘤生长和化疗药物治疗具有重要意义。
The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27(Kip1) and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110 gamma subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3K gamma signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.