Department of Neurosurgery, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, TX 77030, USA.
J Neurooncol. 2012 Feb;106(3):531-42. doi: 10.1007/s11060-011-0707-1. Epub 2011 Sep 21.
Regulation of mRNA decay is an important mechanism controlling gene expression. Steady state levels of mRNAs can be markedly altered by changes in the decay rate. The control of mRNA stability depends on sequences in the transcript itself and on RNA-binding proteins that dynamically bind to these sequences. A well characterized sequence motif, which has been shown to be present in many short-lived mRNAs, is the de-stabilizing adenylate/uridylate-rich element (ARE) located at the 3' untranslated region (3'UTR) of mRNAs. HuR is an RNA-binding protein, which binds to AREs and in doing so, increases the half-life and steady state levels of the corresponding mRNA. Using tissue microarray technology, we found that HuR is over-expressed in human gliomas. We also found that there is a change in HuR localization from being solely in the nucleus to being expressed at high levels in the cytosol. Moreover, a positive correlation was found between total HuR levels, cytosolic localization and tumor grade. We also studied the decay rate of several HuR target mRNAs and found that these mRNAs have a slower rate of decay in glioma cell lines than in astrocytes. Finally, we have been able to decrease both the stability and steady state level of these transcripts in glioma cells using an RNA decoy. More importantly, the decoy transfected cells and cells exposed to a HuR inhibitor have reduced cell growth. In addition, pharmacological inhibition of HuR also resulted in glioma cell growth inhibition. In conclusion, our data suggest that post-transcriptional control abnormalities mediated by HuR are necessary to sustain the rapid growth of this devastating type of cancer.
mRNA 衰变的调控是控制基因表达的重要机制。mRNA 的衰变率变化可显著改变其在细胞内的稳态水平。mRNA 稳定性的调控取决于转录本本身的序列和动态结合这些序列的 RNA 结合蛋白。一个特征明确的序列基序，已经在许多半衰期短的 mRNAs 中被发现，就是位于 mRNA 3'非翻译区（3'UTR）的去稳定腺苷酸/尿苷酸丰富元件（ARE）。HuR 是一种 RNA 结合蛋白，它与 ARE 结合，从而增加相应 mRNA 的半衰期和稳态水平。通过组织微阵列技术，我们发现 HuR 在人类神经胶质瘤中过度表达。我们还发现 HuR 的定位从仅在核内表达转变为在细胞质中高水平表达。此外，HuR 水平、细胞质定位与肿瘤分级之间存在正相关。我们还研究了几个 HuR 靶 mRNA 的衰变率，发现这些 mRNA 在神经胶质瘤细胞系中的衰变率比在星形胶质细胞中慢。最后，我们能够使用 RNA 诱饵降低这些转录物在神经胶质瘤细胞中的稳定性和稳态水平。更重要的是，转染 RNA 诱饵的细胞和暴露于 HuR 抑制剂的细胞的生长都减少了。此外，HuR 的药理学抑制也导致神经胶质瘤细胞生长抑制。总之，我们的数据表明，HuR 介导的转录后控制异常对于维持这种毁灭性癌症的快速生长是必要的。
