FBXO11 represses cellular response to hypoxia by destabilizing hypoxia-inducible factor-1α mRNA
FBXO11 represses cellular response to hypoxia by destabilizing hypoxia-inducible factor-1α mRNA
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DOI：
10.1016/j.bbrc.2015.07.037
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发表时间：
2015-09-04
影响因子：
3.1
通讯作者：
Chun, Yang-Sook
中科院分区：
文献类型：
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作者：
Ju, Uk-Il;Park, Jong-Wan;Chun, Yang-Sook
转录因子缺氧诱导因子-1 α（HIF-1 α）在缺氧条件下被诱导，并在癌症进展和血管生成中起关键作用。蛋白质精氨酸甲基转移酶（PRMTs）通过在翻译后水平催化精氨酸甲基化来调节多种蛋白质的功能，目前已发现11种PRMTs。PRMT 9（或者称为FBXO 11）和PRMT 11（FBXO 10）预期通过其F盒结构域具有E3泛素连接酶活性以及甲基转移酶活性。鉴于先前的研究检查了8种PRMT同种型（PRMT 1 -8）在HIF-1信号通路中的作用，PRMT 1和PRMT 5被证明以相反的方式调节HIF-1 α表达。我们在此研究了FBXO 10和FBXO 11是否参与HIF-1信号通路。因此，siRNA介导的FBXO 11敲低促进了各种癌细胞中HIF-1 α的表达和HIF-1驱动的基因表达，但FBXO 10敲低没有。在机制上，发现FBXO 11通过使HIF-1 α mRNA不稳定来抑制HIF-1 α蛋白的从头合成。由于缺乏F-box的FBXO 11突变体不能通过FBXO 11敲低逆转HIF-1 α的表达，因此FBXO 11对HIF-1 α的调节可能归因于控制HIF-1 α mRNA稳定性的一些蛋白质的泛素化。考虑到HIF-1 α的致癌作用，FBXO 11被认为是肿瘤抑制因子，也是癌症治疗的潜在靶点。(C)由Elsevier Inc.出版。
The transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) is induced under hypoxia and plays crucial roles in cancer progression and angiogenesis. Protein arginine methyltransferases (PRMTs), 11 isoforms of which have been identified so far, modulates the functions of diverse proteins by catalyzing arginine methylation in post-translational level. PRMT9 (alternatively named FBXO11) and PRMT11 (FBXO10) are expected to have the E3 ubiquitin ligase activity through their F-box domains as well as the methyltrasferase activity. Given previous studies examining roles of 8 PRMT isoforms (PRMT1-8) in the HIF-1 signaling pathway, PRMT1 and PRMT5 were demonstrated to regulate HIF-1 alpha expression in opposite ways. We herein examined if FBXO10 and FBXO11 participate in the HIF-1 signaling pathway. Consequently, the siRNA-mediated knockdown of FBXO11 facilitated HIF-1 alpha expression in various cancer cells and HIF-1-driven gene expressions, but the FBXO10 knockdown did not. Mechanistically, FBXO11 was found to inhibit de novo synthesis of HIF-1 alpha protein by destabilizing HIF-1 alpha mRNA. Since a FBXO11 mutant lacking F-box failed to reverse the HIF-1 alpha expression by FBXO11 knockdown, the FBXO11 regulation of HIF-1 alpha may be attributed to the ubiquitination of some proteins controlling HIF-1 alpha mRNA stability. Considering the oncogenic roles of HIF-1 alpha, FBXO11 is suggested to act as a tumor suppressor and also to be a potential target for cancer therapy. (C) 2015 Published by Elsevier Inc.