Microtubule disruption targets HIF-1alpha mRNA to cytoplasmic P-bodies for translational repression.
Microtubule disruption targets HIF-1alpha mRNA to cytoplasmic P-bodies for translational repression.
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DOI：
10.1083/jcb.201004145
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发表时间：
2011-01-10
期刊：
影响因子：
--
通讯作者：
Giannakakou P
中科院分区：
文献类型：
--
作者：
Carbonaro M;O'Brate A;Giannakakou P
HIF-1α的主动翻译需要HIF mRNA在动态微管上的结合和运输，而微管破坏通过将其mRNA从多核糖体释放并将其隔离到P体来抑制HIF-1α的翻译。缺氧诱导因子1α（HIF-1α）在实体瘤中过表达，驱动肿瘤血管生成和存活。然而，实体瘤中HIF-1α表达的调控机制尚不完全清楚。在这项研究中，我们发现微管的完整性和动力学复杂地参与了HIF-1α的翻译。HIF-1α信使RNA（mRNA）在其主动翻译时在动态微管上运输。紫杉醇（taxol，TX）和其他微管靶向药物对微管的干扰可以阻止HIF-1α mRNA的转运，使其从多聚体中释放出来，从而抑制其翻译。微管破坏后P体成分Argonaute 2（Ago 2）的免疫沉淀显示HIF-1α mRNA和HIF靶向microRNA（miRNA）的显著富集。抑制HIF-抑制性miRNA或Ago 2敲除会消除TX抑制HIF-1α翻译的能力。有趣的是，诺考达唑洗脱后的微管再聚合允许HIF-1α mRNA重新进入主动翻译，这表明微管动力学对HIF-1α翻译施加了紧密但可逆的控制。总之，我们为微管依赖性HIF-1α翻译的新机制提供了证据，对细胞生物学具有重要意义。
Active translation of HIF-1α requires association and trafficking of HIF mRNA on dynamic microtubules, whereas microtubule disruption represses HIF-1α translation by releasing its mRNA from polysomes and sequestering it to P-bodies. The hypoxia inducible factor 1α (HIF-1α) is overexpressed in solid tumors, driving tumor angiogenesis and survival. However, the mechanisms regulating HIF-1α expression in solid tumors are not fully understood. In this study, we find that microtubule integrity and dynamics are intricately involved in orchestrating HIF-1α translation. HIF-1α messenger RNA (mRNA) traffics on dynamic microtubules when it is actively translated. Microtubule perturbation by taxol (TX) and other microtubule-targeting drugs stalls HIF-1α mRNA transport and releases it from polysomes, suppressing its translation. Immunoprecipitation of the P-body component Argonaute 2 (Ago2) after microtubule disruption shows significant enrichment of HIF-1α mRNAs and HIF-targeting microRNAs (miRNAs). Inhibition of HIF-repressing miRNAs or Ago2 knockdown abrogates TX’s ability to suppress HIF-1α translation. Interestingly, microtubule repolymerization after nocodazole washout allows HIF-1α mRNA to reenter active translation, suggesting that microtubule dynamics exert tight yet reversible control over HIF-1α translation. Collectively, we provide evidence for a new mechanism of microtubule-dependent HIF-1α translation with important implications for cell biology.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1073/pnas.2233244100
发表时间：
2003-11-11
影响因子：
11.1
作者：
Bratu, DP;Cha, BJ;Tyagi, S
通讯作者：
Tyagi, S
影响因子：
11.2
作者：
Escuin, D;Kline, ER;Giannakakou, P
通讯作者：
Giannakakou, P
影响因子：
4.3
作者：
Escuin, Daniel;Burke, Patricia A.;Giannakakou, Paraskevi
通讯作者：
Giannakakou, Paraskevi
影响因子：
21.3
作者：
Giannakakou, P;Sackett, DL;Fojo, T
通讯作者：
Fojo, T