An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation
An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation
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DOI：
10.1038/onc.2008.370
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发表时间：
2009-01-08
期刊：
影响因子：
8
通讯作者：
Verde, P.
中科院分区：
文献类型：
--
作者：
Talotta, F.;Cimmino, A.;Verde, P.
转录因子AP-1在肿瘤发生中发挥关键作用，通过调节多种蛋白质编码基因，涉及多种癌症特征。在非编码基因中，尚未发现AP-1在肿瘤发生中的靶标。MicroRNAs （miRNAs）是蛋白质编码基因的负转录后调节因子。miRNA表达特征与癌症高度相关，一些肿瘤相关的miRNA （oncomir）在肿瘤发生中起着关键作用。在这里，我们发现实体肿瘤中最常上调的miRNA miR-21是由AP-1诱导的，以响应RAS。通过分析验证的miR-21靶点，我们发现肿瘤抑制因子PTEN和PDCD4以AP-1和miR-21依赖的方式被RAS下调。我们进一步表明，考虑到PDCD4作为AP-1的负调节因子的作用，mir -21介导的PDCD4下调对于RAS反应中最大程度地诱导AP-1活性至关重要。我们的数据揭示了RAS转化中AP-1复合体的正向自动调节的新机制，并揭示了肿瘤细胞在肿瘤发生过程中作为AP-1的关键靶点和调节因子的功能。
The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1- and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.