Wnt-5a mRNA translation is suppressed by the Elav-like protein HuR in human breast epithelial cells.
Wnt-5a mRNA translation is suppressed by the Elav-like protein HuR in human breast epithelial cells.
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DOI：
10.1093/nar/gkl571
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发表时间：
2006
影响因子：
14.9
通讯作者：
Andersson T
中科院分区：
文献类型：
--
作者：
Leandersson K;Riesbeck K;Andersson T
Wnt-5a 是一种非转化 Wnt 蛋白。由于 Wnt-5a mRNA 和蛋白质水平在肿瘤内部和肿瘤之间存在差异，因此 Wnt-5a 作为预后因素的潜力一直存在争议。我们之前已经证明，Wnt-5a 蛋白的缺乏是人类乳腺癌无病生存期较短的预测因素。然而，最近我们还表明，缺乏 Wnt-5a 蛋白的乳腺肿瘤具有高水平或正常水平的 Wnt-5a mRNA，这可能解释了先前研究中的差异。我们在这里报告 Wnt-5a 在转录后水平受到调节。这种调节是由胚胎致死异常视觉 (ELAV) 样蛋白 HuR 介导的，当与 Wnt-5a mRNA 分子 3'-非翻译区 (3'-UTR) 中高度保守的 AU 丰富序列结合时，HuR 会抑制 Wnt-5a 的翻译，如 HA 标记的 Wnt-5a- 和荧光素酶-Wnt-5a-3'-UTR 报告基因检测所示。 HuR 依赖性 Wnt-5a 抑制得到以下事实的支持：活性 HuR 位于侵袭性人类乳腺肿瘤的细胞质中，缺氧诱导的 HuR 激活抑制荧光素酶-Wnt-5a-3'-UTR 和内源性 Wnt-5a 蛋白的翻译。我们提出，侵袭性人类乳腺肿瘤中 Wnt-5a 蛋白表达的缺乏是由 HuR 介导的 Wnt-5a mRNA 翻译抑制引起的。
Wnt-5a is a non-transforming Wnt protein. Since Wnt-5a mRNA and protein levels differ within and between tumours, the potential of Wnt-5a as a prognostic factor has been debated. We have previously shown that the lack of Wnt-5a protein is a predictor of shorter disease-free survival in human breast cancer. Recently, however, we also showed that the breast tumours lacking Wnt-5a protein had a high or normal level of Wnt-5a mRNA that might explain the discrepancies in previous studies. We here report that Wnt-5a is regulated at the post-transcriptional level. The regulation was mediated by the Embryonic Lethal Abnormal Vision (ELAV)-like protein HuR, which inhibited translation of Wnt-5a when bound to highly conserved AU-rich sequences in the 3′-untranslated region (3′-UTR) of the Wnt-5a mRNA molecule, as shown by both HA-tagged Wnt-5a- and Luciferase-Wnt-5a-3′-UTR reporter assays. The HuR-dependent inhibition of Wnt-5a was supported by the fact that active HuR is located in the cytoplasm in invasive human breast tumours and that hypoxia-induced activation of HuR inhibits translation of both Luciferase-Wnt-5a-3′-UTR and endogenous Wnt-5a protein. We propose that the lack of Wnt-5a protein expression in invasive human breast tumours is caused by a HuR-mediated suppression of Wnt-5a mRNA translation.
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