Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma.
Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma.
复制标题
肿瘤抑制因子 Pdcd4 减弱 Sin1 翻译以抑制结肠癌的侵袭
DOI：
10.1038/onc.2017.228
复制
发表时间：
2017-11-09
期刊：
影响因子：
8
通讯作者：
Yang HS
中科院分区：
文献类型：
--
作者：
Wang Q;Zhu J;Wang YW;Dai Y;Wang YL;Wang C;Liu J;Baker A;Colburn NH;Yang HS
程序性细胞死亡4 （Pdcd4）是一种肿瘤侵袭抑制因子，在结直肠癌和其他癌症中经常下调。在这项研究中，我们发现Pdcd4的缺失增加了哺乳动物雷帕霉素靶蛋白复合物2 （mTORC2）的活性，从而上调了蜗牛的表达。检测mTORC2的成分发现，Pdcd4敲低增加了应激激活蛋白激酶相互作用蛋白1 （Sin1）的蛋白水平，但没有增加Sin1的mRNA水平，这是由于Sin1翻译增强所致。为了了解Pdcd4调控Sin1翻译的机制，我们将Sin1的5 ‘非翻译区（5 ’ utr）与荧光素酶报告基因融合，命名为5 ' Sin1- luc。Pdcd4敲低/敲除显著增加了5'Sin1-Luc的翻译，但没有增加没有sin15 ' utr的对照荧光素酶的翻译，这表明sin15 ' utr是Pdcd4抑制SIN1翻译所必需的。野生型Pdcd4和结合翻译起始因子4A （eIF4A）的缺失突变体Pdcd4（157-469）的异位表达充分抑制了Sin1的翻译，从而抑制了mTORC2激酶的活性和结肠癌肿瘤细胞的侵袭。相比之下，Pdcd4(157-469)(D253A,D418A)，一个不结合eIF4A的突变体，不能抑制Sin1的翻译，因此不能抑制mTORC2的活性和侵袭。此外，用西尔维斯特醇直接抑制eIF4A可显著抑制Sin1翻译，减弱侵袭。这些结果表明pdcd4抑制Sin1翻译是通过抑制eIF4A实现的，对抑制mTORC2活性和侵袭具有重要的功能。此外，在结直肠癌组织中，Sin1蛋白而非mRNA显著上调，Pdcd4蛋白显著下调，提示结直肠癌患者中Pdcd4的缺失可能与Sin1蛋白水平相关，而与mRNA水平无关。综上所述，我们的工作揭示了Pdcd4抑制Sin1翻译以减弱torc2活性从而抑制入侵的新机制。
Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently down-regulated in colorectal cancer and other cancers. In this study, we find that loss of Pdcd4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the SIN1 5’ untranslated region (5’UTR) was fused with luciferase reporter and named as 5’Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation of 5’Sin1-Luc but not the control luciferase without the SIN1 5’UTR, suggesting that Sin1 5’UTR is necessary for Pdcd4 to inhibit Sin1 translation. Ectopic expression of wild type Pdcd4 and Pdcd4(157–469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited Sin1 translation, and thus suppressed mTORC2 kinase activity and invasion in colon tumor cells. By contrast, Pdcd4(157–469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and consequently failed to repress mTORC2 activity and invasion. In addition, directly inhibiting eIF4A with silvestrol significantly suppressed Sin1 translation and attenuated invasion. These results indicate that Pdcd4-inhibited Sin1 translation is through suppressing eIF4A, and functionally important for suppression of mTORC2 activity and invasion. Moreover, in colorectal cancer tissues, the Sin1 protein but not mRNA was significantly up-regulated while Pdcd4 protein was down-regulated, suggesting that loss of Pdcd4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which Pdcd4 inhibits Sin1 translation to attenuatemTORC2 activity and thereby suppresses invasion.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-09-1249
发表时间：
2009-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gulhati P;Cai Q;Li J;Liu J;Rychahou PG;Qiu S;Lee EY;Silva SR;Bowen KA;Gao T;Evers BM
通讯作者：
Evers BM
影响因子：
37.3
作者：
Roulin D;Cerantola Y;Dormond-Meuwly A;Demartines N;Dormond O
通讯作者：
Dormond O
影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
MTORC2激酶复合物的PTDINS（3,4,5）P3依赖性激活。
影响因子：
28.2
作者：
Liu P;Gan W;Chin YR;Ogura K;Guo J;Zhang J;Wang B;Blenis J;Cantley LC;Toker A;Su B;Wei W
通讯作者：
Wei W
影响因子：
14.9
作者：
Fehler O;Singh P;Haas A;Ulrich D;Müller JP;Ohnheiser J;Klempnauer KH
通讯作者：
Klempnauer KH