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TGF-β 介导体 hnRNP E1 的磷酸化通过 Dab2 和 ILEI 的转录选择性翻译诱导 EMT。

TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI.

机构信息

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.

出版信息

Nat Cell Biol. 2010 Mar;12(3):286-93. doi: 10.1038/ncb2029. Epub 2010 Feb 14.

DOI:10.1038/ncb2029
PMID:20154680
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2830561/
Abstract

Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, the identification of TGF-beta-inducible, EMT-specific genes has met with limited success. Here we identify a post-transcriptional pathway by which TGF-beta modulates the expression of EMT-specific proteins and of EMT itself. We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation. TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. Modulation of hnRNP E1 expression or its post-translational modification alters the TGF-beta-mediated reversal of translational silencing of the target transcripts and EMT. These results suggest the existence of a TGF-beta-inducible post-transcriptional regulon that controls EMT during the development and metastatic progression of tumours.

摘要

转化生长因子-β（TGF-β）诱导上皮-间充质转化（EMT），伴随细胞分化和迁移。尽管进行了广泛的转录组分析，但鉴定 TGF-β诱导的 EMT 特异性基因的工作进展有限。在这里，我们确定了 TGF-β调节 EMT 特异性蛋白和 EMT 本身表达的转录后途径。我们表明，异质核核糖核蛋白 E1（hnRNP E1）结合了失活 2（Dab2）和白细胞介素样 EMT 诱导物（ILEI）转录本 3'非翻译区中结构上的 33 个核苷酸 TGF-β激活翻译（BAT）元件，并抑制它们的翻译。TGF-β 激活导致蛋白激酶 Bβ/Akt2 在 hnRNP E1 的丝氨酸 43 位磷酸化，导致其从 BAT 元件释放，并使 Dab2 和 ILEI 信使 RNA 的翻译激活。hnRNP E1 表达或其翻译后修饰的调节改变了 TGF-β介导的靶转录本和 EMT 的翻译沉默的逆转。这些结果表明，存在一个 TGF-β诱导的转录后调节物，它在肿瘤的发育和转移进展过程中控制 EMT。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/840014ca2422/nihms172352f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/d332a111ffd4/nihms172352f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/41668f020096/nihms172352f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/63e9aae97301/nihms172352f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/7608289f988d/nihms172352f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/840014ca2422/nihms172352f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/d332a111ffd4/nihms172352f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/41668f020096/nihms172352f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/63e9aae97301/nihms172352f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/7608289f988d/nihms172352f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c670/2830561/840014ca2422/nihms172352f5.jpg

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