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CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation

机译：CPEB和两个poly（A）聚合酶控制miR-122的稳定性和p53 mRNA的翻译

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摘要

Cytoplasmic polyadenylation-induced translation controls germ cell development, neuronal synaptic plasticity and cellular senescence, a tumour-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) polymerase10"12, on specific messenger RNA (mRNA) 3' untranslated regions (UTRs). Because CPEB regulation of p53 mRNA polyadenyla-tion/translation is necessary for cellular senescence in primary human diploid fibroblasts6, 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/G1d4.
机译：细胞质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，这是一种肿瘤抑制机制，限制了细胞的复制寿命。胞质聚腺苷酸化元素结合蛋白（CPEB）通过在特定信使RNA（mRNA）3'非翻译区上成核，包括种系发育2（Gld2），非规范性poly（A）聚合酶10“ 12的缺陷等因素，促进多腺苷酸化（UTRs）。因为CPEB调节p53 mRNA聚腺苷酸化/翻译对于人类原代二倍体成纤维细胞6的细胞衰老是必需的，所以我们推测Gld2是负责poly（A）添加的酶。促进而不是抑制p53 mRNA的多腺苷酸化/翻译，诱导过早衰老并增强CPEB mRNA的稳定性CPEB 3'UTR包含两个miR-122结合位点，与miR-122的antagomir缺失时，两个结合位点被删除时可提高mRNA的翻译。尽管人们认为miR-122是肝特异性的，但它存在于原代成纤维细胞中，并由于Gld2耗竭而失稳，发现第二个非规范的poly（A）聚合酶Gld4可以以CPEB依赖性方式调节p53 mRNA多聚腺苷酸化/翻译。因此，通过Gld2 / miR-122 / CPEB / G1d4协调p53 mRNA的翻译调控和细胞衰老。

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  • 来源
    《Nature》 |2011年第7345期|p.105-108|共4页
  • 作者

    David M. Burns; Andrea DAmbrogio; Stephanie Nottrott; Joel D. Richter;

  • 作者单位

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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