p53 represses c-Myc through induction of the tumor suppressor miR-145
p53 represses c-Myc through induction of the tumor suppressor miR-145
复制标题
DOI：
10.1073/pnas.0808042106
复制
发表时间：
2009-03-03
影响因子：
11.1
通讯作者：
Mo, Yin-Yuan
中科院分区：
文献类型：
--
作者：
Sachdeva, Mohit;Zhu, Shoumin;Mo, Yin-Yuan
肿瘤抑制因子p53除了激活许多其他基因外，还对包括原癌基因c - Myc在内的一些基因起负调控作用。p53介导的c - Myc抑制的一种机制可能涉及转录调控。然而，尚不清楚微小RNA（miRNAs）是否在p53介导的c - Myc转录后调控中起作用。在这项研究中，我们表明一种假定的肿瘤抑制因子miR - 145通过磷脂酰肌醇 - 3激酶（PI - 3K）/Akt和p53通路表达。重要的是，p53通过与miR - 145启动子中一个潜在的p53反应元件（p53RE）相互作用，转录诱导miR - 145的表达。我们进一步表明c - Myc是miR - 145的一个直接靶标。尽管miR - 145使c - Myc的表达沉默，但抗miR - 145会增强其表达。miR - 145对c - Myc的这种特异性沉默至少在一定程度上解释了miR - 145在体外和体内对肿瘤细胞生长的抑制作用。最后，抗miR - 145对miR - 145的阻断能够逆转p53介导的c - Myc抑制。总之，这些结果明确了miR - 145在p53对c - Myc的转录后调控中的作用，并表明作为p53调控网络的一个新成员，miR - 145在这个基因调控网络中提供了p53和c - Myc之间的直接联系。
The tumor suppressor p53 negatively regulates a number of genes, including the proto-oncogene c-Myc, in addition to activating many other genes. One mechanism of the p53-mediated c-Myc repression may involve transcriptional regulation. However, it is not clear whether microRNAs (miRNAs) play a role in the p53-mediated posttranscriptional regulation of c-Myc. In this study, we show that a putative tumor suppressor, miR-145, is expressed through the phosphoinositide-3 kinase (PI-3K)/Akt and p53 pathways. Importantly, p53 transcriptionally induces the expression of miR-145 by interacting with a potential p53 response element (p53RE) in the miR-145 promoter. We further show that c-Myc is a direct target for miR-145. Although miR-145 silences the expression of c-Myc, anti-miR-145 enhances its expression. This specific silencing of c-Myc by miR-145 accounts at least in part for the miR-145-mediated inhibition of tumor cell growth both in vitro and in vivo. Finally, the blockade of miR-145 by anti-miR-145 is able to reverse the p53-mediated c-Myc repression. Together, these results define the role of miR-145 in the posttranscriptional regulation of c-Myc by p53 and suggest that, as a new member of the p53 regulatory network, miR-145 provides a direct link between p53 and c-Myc in this gene regulatory network.