Phosphorylation of HuR by Chk2 regulates SIRT1 expression
Phosphorylation of HuR by Chk2 regulates SIRT1 expression
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DOI：
10.1016/j.molcel.2007.01.011
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发表时间：
2007-02-23
期刊：
影响因子：
16
通讯作者：
Gorospe, Myriam
中科院分区：
文献类型：
--
作者：
Abdelmohsen, Kotb;Pullmann, Rudolf, Jr.;Gorospe, Myriam
RNA结合蛋白HuR调节许多靶mrna的稳定性。在这里，我们报道了HuR与编码长寿和应激反应蛋白SIRT1的mRNA的3'非翻译区相关，稳定了SIRT1 mRNA，并增加了SIRT1的表达水平。出乎意料的是，氧化应激触发了[HuR-SIRT1 mRNA]复合物的解离，进而促进SIRT1 mRNA的衰变，降低SIRT1丰度，降低细胞存活率。细胞周期检查点激酶Chk2被H2O2激活，与HuR相互作用，并预测在残基S88， S100和T118磷酸化HuR。这些残基的突变揭示了HuR结合的复杂模式，其中S100似乎对H2O2后[HuR- sirt1 mRNA]的解离很重要。我们的研究结果表明，HuR调节SIRT1的表达，强调了两种应激反应蛋白之间的功能联系，并暗示Chk2在这些过程中。
The RNA binding protein HuR regulates the stability of many target mRNAs. Here, we report that HuR associated with the 3' untranslated region of the mRNA encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidative stress triggered the dissociation of the [HuR-SIRT1 mRNA] complex, in turn promoting SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival. The cell cycle checkpoint kinase Chk2 was activated by H2O2, interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H2O2. Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes.