A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis.
A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis.
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人类癌症中的大多数 p53 突变都是错义突变，导致全长突变 p53 蛋白。除了失去肿瘤抑制活性外，一些热点 p53 突变体还获得了致癌功能。这种效应部分是通过靶基因启动子处的突变型 p53 抑制 p63 和 p73 导致的基因表达变化来介导的。在这里，我们报告在表达内源突变体 p53 的多个细胞系中，肿瘤抑制因子 microRNA let-7i 被突变体 p53 下调。在乳腺癌患者中，let-7i 水平显着降低与 p53 错义突变相关。染色质免疫沉淀和启动子荧光素酶测定将 let-7i 确定为突变体 p53 至 p63 的转录靶标。将let-7i引入突变p53细胞可通过抑制E2F5、LIN28B、MYC和NRAS等癌基因网络显着抑制迁移、侵袭和转移。我们的研究结果表明，突变体 p53 对 let-7i 表达的抑制在增强迁移、侵袭和转移方面具有关键作用。
Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
捕获microRNA结合的mRNA将肿瘤抑制器miR-34a识别为生长因子信号传导的调节剂。
影响因子：
4.5
作者：
Lal A;Thomas MP;Altschuler G;Navarro F;O'Day E;Li XL;Concepcion C;Han YC;Thiery J;Rajani DK;Deutsch A;Hofmann O;Ventura A;Hide W;Lieberman J
通讯作者：
Lieberman J
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：
16
作者：
Lal A;Navarro F;Maher CA;Maliszewski LE;Yan N;O'Day E;Chowdhury D;Dykxhoorn DM;Tsai P;Hofmann O;Becker KG;Gorospe M;Hide W;Lieberman J
通讯作者：
Lieberman J
影响因子：
16.8
作者：
Chi, Sung Wook;Hannon, Gregory J.;Darnell, Robert B.
通讯作者：
Darnell, Robert B.