TRAP1-dependent regulation of p70S6K is involved in the attenuation of protein synthesis and cell migration: Relevance in human colorectal tumors
TRAP1-dependent regulation of p70S6K is involved in the attenuation of protein synthesis and cell migration: Relevance in human colorectal tumors
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DOI：
10.1016/j.molonc.2014.06.003
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发表时间：
2014-12-01
影响因子：
6.6
通讯作者：
Esposito, Franca
中科院分区：
文献类型：
--
作者：
Matassa, Danilo Swann;Agliarulo, Ilenia;Esposito, Franca
肿瘤坏死因子受体相关蛋白1（TRAP 1）是一种热休克蛋白90分子伴侣，参与线粒体和线粒体外区室的应激保护和凋亡。值得注意的是，在几种癌症类型中观察到TRAP 1功能的异常失调，这为人类的治疗干预提供了潜在的新机会。虽然我们小组以前的研究确定了TRAP 1通过减弱蛋白质合成在质量控制中的新作用，但分子机制在很大程度上仍然未知。为了进一步阐明TRAP 1在减弱蛋白质合成中调节的信号通路，本研究表明，在TRAP 1干扰后，细胞中帽介导的翻译的整个通路被激活：一致地，在TRAP 1沉默后，两种翻译激活激酶p70 S6 K和RSK 1的表达和随后的磷酸化增加。此外，我们表明，这些调节功能影响伤口愈合试验中的翻译应力和细胞迁移的反应，涉及这两种激酶的过程。值得注意的是，由TRAP 1控制的调节机制在结直肠癌组织中是保守的，因为在肿瘤组织中发现TRAP 1和p70 S6 K表达之间的负相关性，从而支持TRAP 1在体内翻译调节的相关作用。总的来说，这些新发现候选TRAP 1网络用于新的抗癌策略，旨在靶向肿瘤细胞的翻译/质量控制机制。(C)2014年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
TNF receptor-associated protein 1 (TRAP1) is an HSP90 chaperone involved in stress protection and apoptosis in mitochondrial and extramitochondrial compartments. Remarkably, aberrant deregulation of TRAP1 function has been observed in several cancer types with potential new opportunities for therapeutic intervention in humans. Although previous studies by our group identified novel roles of TRAP1 in quality control of mitochondria-destined proteins through the attenuation of protein synthesis, molecular mechanisms are still largely unknown. To shed further light on the signaling pathways regulated by TRAP1 in the attenuation of protein synthesis, this study demonstrates that the entire pathway of cap-mediated translation is activated in cells following TRAP1 interference: consistently, expression and consequent phosphorylation of p70S6K and RSK1, two translation activating kinases, are increased upon TRAP1 silencing. Furthermore, we show that these regulatory functions affect the response to translational stress and cell migration in wound healing assays, processes involving both kinases. Notably, the regulatory mechanisms controlled by TRAP1 are conserved in colorectal cancer tissues, since an inverse correlation between TRAP1 and p70S6K expression is found in tumor tissues, thereby supporting the relevant role of TRAP1 translational regulation in vivo. Taken as a whole, these new findings candidate TRAP1 network for new anti-cancer strategies aimed at targeting the translational/quality control machinery of tumor cells. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.