CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation.
CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation.
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DOI：
10.1038/nature09908
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发表时间：
2011-05-05
期刊：
影响因子：
64.8
通讯作者：
Richter, Joel D.
中科院分区：
文献类型：
--
作者：
Burns, David M.;D'Ambrogio, Andrea;Nottrott, Stephanie;Richter, Joel D.
胞质多聚腺苷酸化诱导的翻译控制生殖细胞发育、神经元突触可塑性和细胞衰老，这是一种限制细胞复制寿命的肿瘤抑制机制。胞质多聚腺苷酸化元件结合蛋白（CPEB）通过在特定mRNA 3'非翻译区（UTR）上使一组因子成核来促进多聚腺苷酸化，所述因子包括生殖系发育缺陷2（Gld 2），一种非典型的多聚腺苷酸聚合酶。因为CPEB调节p53 mRNA多聚腺苷酸化/翻译是原代人二倍体成纤维细胞衰老所必需的，我们推测Gld 2将是负责poly（A）添加的酶。在这里，我们发现，Gld 2的耗竭令人惊讶地促进而不是抑制p53 mRNA的多聚腺苷酸化/翻译，诱导早衰，并提高CPEB mRNA的稳定性。CPEB 3 'UTR含有两个miR-122结合位点，当其缺失时，提高mRNA翻译，就像miR-122的一个非翻译区一样。虽然miR-122被认为是肝脏特异性的，但它存在于原代成纤维细胞中，并因Gld 2耗尽而不稳定。Gld 4是第二种非典型的poly（A）聚合酶，它以CPEB依赖的方式调节p53 mRNA的聚腺苷酸化/翻译。因此，p53 mRNA的翻译调节和细胞衰老由Gld 2/miR-122/CPEB/Gld 4协调。
Cytoplasmic polyadenylation-induced translation controls germ cell development, neuronal synaptic plasticity, and cellular senescence, a tumor-suppressor mechanism that limits the replicative lifespan of cells . The cytoplasmic polyadenylation element binding protein (CPEB) promotes polyadenylation by nucleating a group of factors including defective in germline development 2 (Gld2), a non-canonical poly(A) polymerase, on specific mRNA 3’ untranslated regions (UTRs). Because CPEB regulation of p53 mRNA polyadenylation/translation is necessary for cellular senescence in primary human diploid fibroblasts, we surmised that Gld2 would be the enzyme responsible for poly(A) addition. Here, we show that depletion of Gld2 surprisingly promotes rather than inhibits p53 mRNA polyadenylation/translation, induces premature senescence, and enhances the stability of CPEB mRNA. The CPEB 3’UTR contains two miR-122 binding sites, which when deleted, elevate mRNA translation, as does an antagomir of miR-122. Although miR-122 is thought to be liver-specific, it is present in primary fibroblasts and destabilized by Gld2 depletion. Gld4, a second non-canonical poly(A) polymerase, was found to regulate p53 mRNA polyadenylation/translation in a CPEB-dependent manner. Thus, translational regulation of p53 mRNA and cellular senescence is coordinated by Gld2/miR-122/CPEB/Gld4.
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影响因子：
3.7
作者：
Liao JY;Ma LM;Guo YH;Zhang YC;Zhou H;Shao P;Chen YQ;Qu LH
通讯作者：
Qu LH
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
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作者：
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作者：
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