The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response
The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response
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DOI：
10.1073/pnas.0906947106
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发表时间：
2009-09-15
影响因子：
11.1
通讯作者：
Stebbing, Justin
中科院分区：
文献类型：
--
作者：
Castellano, Leandro;Giamas, Georgios;Stebbing, Justin
雌激素激活后，雌激素受体α（ER α）通过DNA结合直接调节靶基因的转录。由ER α调节的microRNA（miRNAs）具有微调这些调节系统的潜力，并且还提供了可能影响雌激素依赖性发育和病理系统的替代机制。通过微阵列的方法，我们确定了由ER α调节的microRNA（miRNA）的子集，其中包括源自旁系同源初级转录物（pri-）mir-17-92和mir-106 a-363的加工的miRNA的上调。mir-17-92位点的表征证实ER α靶蛋白c-MYC以雌激素依赖性方式结合其启动子。我们观察到pri-mir-17-92的水平比其衍生的成熟miRNAs更早增加，暗示转录后的前体切割调节。Pri-mir-17-92立即被DROSHA切割为pre-miR-18 a，表明其调节发生在从前体形成成熟分子的过程中。通过证明与ER α阴性乳腺癌相比，ER α阳性乳腺癌中pre-miR-18 a显著上调，证实了这种新型调控系统的临床意义。从机制上讲，源自这些旁系同源pri-miRNA（miR-18 a、miR-19 b和miR-20 b）的miRNA靶向并下调ER α，而pri-miRNA衍生的miRNA的子集抑制ER α转录p160共激活因子AIB 1的蛋白质翻译。因此，鉴定的不同miRNA子集作为负性自动调节反馈环的一部分。我们认为ER α、c-MYC和miRNA转录程序引发了一个复杂的相互作用网络，能够提供广泛的协调细胞对雌激素的反应。
Following estrogenic activation, the estrogen receptor-alpha (ER alpha) directly regulates the transcription of target genes via DNA binding. MicroRNAs ( miRNAs) modulated by ER alpha have the potential to fine tune these regulatory systems and also provide an alternate mechanism that could impact on estrogen-dependent developmental and pathological systems. Through a microarray approach, we identify the subset of microRNAs ( miRNAs) modulated by ER alpha, which include upregulation of miRNAs derived from the processing of the paralogous primary transcripts (pri-) mir-17-92 and mir-106a-363. Characterization of the mir-17-92 locus confirms that the ER alpha target protein c-MYC binds its promoter in an estrogen-dependent manner. We observe that levels of pri-mir-17-92 increase earlier than the mature miRNAs derived from it, implicating precursor cleavage modulation after transcription. Pri-mir-17-92 is immediately cleaved by DROSHA to pre-miR-18a, indicating that its regulation occurs during the formation of the mature molecule from the precursor. The clinical implications of this novel regulatory system were confirmed by demonstrating that pre-miR-18a was significantly upregulated in ER alpha-positive compared to ER alpha-negative breast cancers. Mechanistically, miRNAs derived from these paralogous pri- miRNAs (miR-18a, miR-19b, and miR-20b) target and downregulate ER alpha, while a subset of pri-miRNA-derived miRNAs inhibit protein translation of the ER alpha transcriptional p160 coactivator, AIB1. Therefore, different subsets of miRNAs identified act as part of a negative autoregulatory feedback loop. We propose that ER alpha, c-MYC, and miRNA transcriptional programs invoke a sophisticated network of interactions able to provide the wide range of coordinated cellular responses to estrogen.