Selective degradation of AU-rich mRNAs promoted by the p37 AUF1 protein isoform
Selective degradation of AU-rich mRNAs promoted by the p37 AUF1 protein isoform
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DOI：
10.1128/mcb.23.18.6685-6693.2003
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发表时间：
2003-09-01
影响因子：
5.3
通讯作者：
Schneider, RJ
中科院分区：
文献类型：
--
作者：
Sarkar, B;Xi, QR;Schneider, RJ
由重复的典型AUUUA基序组成的富含AU的元件（ARE）当存在于3'非翻译区中时赋予许多细胞因子mRNA快速降解。用战神（ARE-mRNAs）使mRNAs失稳与ARE结合蛋白如tristetraprolin和四种AUF 1亚型的相互作用一致。然而，AUF 1-mRNA相互作用与ARE-mRNA稳定性降低的相关性是相关的，尚未直接测试。因此，我们确定了AUF 1亚型的过表达是否促进了ARE-mRNA的不稳定，以及AUF 1亚型是否是ARE-mRNA衰变的限制性组分。我们发现，p37 AUF 1亚型，并在较小程度上，p40亚型具有ARE-mRNA的不稳定活性时，过表达。令人惊讶的是，过表达的p37 AUF 1也使含有非典型但富含AU的3'非翻译区的报告mRNA不稳定。由于过表达的p37 AUF 1可以在体内与富含AU的报告基因mRNA相互作用，AUF 1可能参与缺乏典型战神的mRNA的快速周转。此外，p37 AUF 1的过表达恢复了细胞快速降解ARE-mRNA的能力，当这种能力被ARE-mRNA的过表达饱和和抑制时。最后，ARE-mRNA衰变的激活通常涉及一个依赖于抑制的步骤，这是通过p37 AUF 1的过表达消除的。这些数据表明，p37 AUF 1亚型，在某种程度上，p40亚型是限制因素，促进快速衰减的AU丰富的mRNA。
An AU-rich element (ARE) consisting of repeated canonical AUUUA motifs confers rapid degradation to many cytokine mRNAs when present in the 3' untranslated region. Destabilization of mRNAs with AREs (ARE-mRNAs) is consistent with the interaction of ARE-binding proteins such as tristetraprolin and the four AUF1 isoforms. However, the association of the AUF1-mRNA interaction with decreased ARE-mRNA stability is correlative and has not been directly tested. We therefore determined whether overexpression of AUF1 isoforms promotes ARE-mRNA destabilization and whether AUF1 isoforms are limiting components for ARE-mRNA decay. We show that the p37 AUF1 isoform, and, to a lesser extent, the p40 isoform possess ARE-mRNA-destabilizing activity when overexpressed. Surprisingly, overexpressed p37 AUF1 also destabilized reporter mRNAs containing a noncanonical but AU-rich 3' untranslated region. Since overexpressed p37 AUF1 could interact in vivo with the AU-rich reporter mRNA, AUF1 may be involved in rapid turnover of mRNAs that lack canonical AREs. Moreover, overexpression of p37 AUF1 restored the ability of cells to rapidly degrade ARE-mRNAs when that ability was saturated and inhibited by overexpression of ARE-mRNAs. Finally, activation of ARE-mRNA decay often involves a translation-dependent step, which was eliminated by overexpression of p37 AUF1. These data indicate that the p37 AUF1 isoform and, to some extent, the p40 isoform are limiting factors that facilitate rapid decay of AU-rich mRNAs.