MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells.
MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells.
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DOI：
10.1038/onc.2011.343
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发表时间：
2012-03-15
期刊：
影响因子：
8
通讯作者：
Zhou, M.
中科院分区：
文献类型：
--
作者：
Gu, L.;Zhang, H.;He, J.;Li, J.;Huang, M.;Zhou, M.
MYCN基因在决定神经母细胞瘤的临床行为中起着关键作用。虽然已知基因组扩增发生在高危亚群中，但仍不清楚MYCN表达在神经母细胞瘤发病机制中如何调节。在此，我们报告MYCN表达在转录后水平受癌蛋白MDM2调控，并与神经母细胞瘤细胞生长相关。通过在细胞质中异位过表达增加MDM2增强MYCN的mRNA和蛋白表达。机制研究发现，MDM2蛋白的C端RING结构域与MYCN mRNA 3′非翻译区（3′UTR）内富含AU的元件结合，并增加MYCN 3′ UTR介导的mRNA稳定性和翻译。相反，通过特异性siRNA沉默MDM2使MYCN mRNA不稳定，并降低MYCN扩增的神经母细胞瘤细胞系中MYCN蛋白的丰度。重要的是，这种MDM2沉默导致神经母细胞瘤细胞生长的显著抑制和通过p53非依赖性途径诱导细胞死亡。我们的研究结果表明，MDM2在MYCN mRNA稳定及其翻译的调节中起着p53非依赖性作用，这表明MDM2介导的MYCN表达是与MYCN相关神经母细胞瘤生长和疾病进展相关的一种机制。
The MYCN gene plays a critical role in determining the clinical behavior of neuroblastoma. Although it is known that genomic amplification occurs in high-risk subsets, it remains unclear how MYCN expression is regulated in the pathogenesis of neuroblastomas. Herein, we report that MYCN expression was regulated by the oncoprotein MDM2 at the post-transcriptional level and was associated with neuroblastoma cell growth. Increasing MDM2 by ectopic overexpression in the cytoplasm enhanced both mRNA and protein expression of MYCN. Mechanistic studies found that the C-terminal RING domain of the MDM2 protein bound to the MYCN mRNA’s AU-rich elements within the 3′-untranslated region (3′UTR) and increased MYCN 3′UTR-mediated mRNA stability and translation. Conversely, MDM2 silencing by specific siRNA rendered the MYCN mRNA unstable and reduced the abundance of MYCN protein in MYCN-amplified neuroblastoma cell lines. Importantly, this MDM2 silencing resulted in a remarkable inhibition of neuroblastoma cell growth and induction of cell death through a p53-independent pathway. Our results indicate that MDM2 plays a p53-independent role in the regulation of both MYCN mRNA stabilization and its translation, suggesting that MDM2-mediated MYCN expression is one mechanism associated with growth of MYCN-associated neuroblastoma and disease progression.
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影响因子：
50.3
作者：
Gu L;Zhu N;Zhang H;Durden DL;Feng Y;Zhou M
通讯作者：
Zhou M
影响因子：
4.8
作者：
Manohar, CF;Short, ML;Cohn, SL
通讯作者：
Cohn, SL
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5.3
作者：
Cobbold, Laura C.;Spriggs, Keith A.;Willis, Anne E.
通讯作者：
Willis, Anne E.
影响因子：
2.9
作者：
Lai, ZH;Freedman, DA;McLendon, GL
通讯作者：
McLendon, GL
影响因子：
56.9
作者：
BRODEUR, GM;SEEGER, RC;BISHOP, JM
通讯作者：
BISHOP, JM