A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition.
A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition.
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DOI：
10.1083/jcb.201103097
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发表时间：
2011-10-31
期刊：
影响因子：
--
通讯作者：
Yook JI
中科院分区：
文献类型：
--
作者：
Kim NH;Kim HS;Li XY;Lee I;Choi HS;Kang SE;Cha SY;Ryu JK;Yoon D;Fearon ER;Rowe RG;Lee S;Maher CA;Weiss SJ;Yook JI
miR-34通过p53依赖性调控途径抑制EMT诱导剂Snail 1的表达。Snail 1是一种锌指转录抑制因子，其病理表达与癌细胞上皮-间质转化（EMT）程序和组织侵袭活性的诱导有关，但能够调节Snail 1活性的促癌事件在很大程度上仍不清楚。在此，我们证明了p53功能丧失或突变通过去抑制Snail 1蛋白表达和活性来促进癌细胞EMT。在缺乏野生型p53功能的情况下，Snail 1依赖性EMT在结肠癌、乳腺癌和肺癌细胞中由于miRNA-34水平的降低而被激活，miRNA-34通过结合Snail 1自身以及关键Snail 1调节分子（包括β-catenin、LEF 1和Axin 2）的高度保守的3′非翻译区来抑制Snail 1活性。虽然p53活性可以影响细胞周期调控、凋亡和DNA修复途径，但由p53功能丧失或突变启动的EMT和侵袭程序完全依赖于Snail 1表达。这些结果确定了p53，miR-34和Snail 1在调节癌细胞EMT程序中的新联系。
Expression of the essential EMT inducer Snail1 is inhibited by miR-34 through a p53-dependent regulatory pathway. Snail1 is a zinc finger transcriptional repressor whose pathological expression has been linked to cancer cell epithelial–mesenchymal transition (EMT) programs and the induction of tissue-invasive activity, but pro-oncogenic events capable of regulating Snail1 activity remain largely uncharacterized. Herein, we demonstrate that p53 loss-of-function or mutation promotes cancer cell EMT by de-repressing Snail1 protein expression and activity. In the absence of wild-type p53 function, Snail1-dependent EMT is activated in colon, breast, and lung carcinoma cells as a consequence of a decrease in miRNA-34 levels, which suppress Snail1 activity by binding to highly conserved 3′ untranslated regions in Snail1 itself as well as those of key Snail1 regulatory molecules, including β-catenin, LEF1, and Axin2. Although p53 activity can impact cell cycle regulation, apoptosis, and DNA repair pathways, the EMT and invasion programs initiated by p53 loss of function or mutation are completely dependent on Snail1 expression. These results identify a new link between p53, miR-34, and Snail1 in the regulation of cancer cell EMT programs.
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影响因子：
11.2
作者：
Chen, Ya-Wen;Klimstra, David S.;Lewis, Brian C.
通讯作者：
Lewis, Brian C.
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.
影响因子：
64.5
作者：
Godar S;Ince TA;Bell GW;Feldser D;Donaher JL;Bergh J;Liu A;Miu K;Watnick RS;Reinhardt F;McAllister SS;Jacks T;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
11.2
作者：
Corney, David C.;Flesken-Nikitin, Andrea;Nikitin, Alexander Yu.
通讯作者：
Nikitin, Alexander Yu.