Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition.
Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition.
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DOI：
10.1083/jcb.200512110
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发表时间：
2006-07-17
影响因子：
7.8
通讯作者：
Moustakas, Aristidis
中科院分区：
文献类型：
--
作者：
Thuault, Sylvie;Valcourt, Ulrich;Petersen, Maj;Manfioletti, Guidalberto;Heldin, Carl-Henrik;Moustakas, Aristidis
上皮-间充质转化发生在胚胎发生、肿瘤侵袭和转移过程中，转化生长因子-β(转化生长因子-β)可通过细胞内Smad转导途径诱导。控制EMT发病的分子机制在很大程度上仍不清楚。转录分析表明，高迁移率族A2(HMGA2)基因是由Smad途径在EMT过程中诱导的。内源性HMGA2通过转化生长因子-β介导EMT，而异位HMGA2则引起以严重抑制E-钙粘附素为特征的不可逆EMT。HMGA2为四种已知的EMT调节因子，锌指蛋白Snail和Slug，基本螺旋-环-螺旋蛋白Twist和分化抑制因子2的表达调控提供转录输入。我们描述了一条途径，将转化生长因子-β信号与通过HMGA2控制上皮细胞分化联系起来，以及一系列肿瘤侵袭和转移的主要调节因子。这一信号/转录因子网络依次作用于建立EMT，这表明对这些蛋白质的组合检测可以作为癌症患者EMT分析的新工具。
Epithelial–mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-β (TGF-β) signaling via intracellular Smad transducers. The molecular mechanisms that control the onset of EMT remain largely unexplored. Transcriptomic analysis revealed that the high mobility group A2 (HMGA2) gene is induced by the Smad pathway during EMT. Endogenous HMGA2 mediates EMT by TGF-β, whereas ectopic HMGA2 causes irreversible EMT characterized by severe E-cadherin suppression. HMGA2 provides transcriptional input for the expression control of four known regulators of EMT, the zinc-finger proteins Snail and Slug, the basic helix-loop-helix protein Twist, and inhibitor of differentiation 2. We delineate a pathway that links TGF-β signaling to the control of epithelial differentiation via HMGA2 and a cohort of major regulators of tumor invasiveness and metastasis. This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients.