| Summary: | 博士 === 國立陽明大學 === 生化暨分子生物研究所 === 99 === Tumor suppressor p53, a transcriptional activator, maintains genome integrity by mediating the expression of downstream targets. Here we show that the Rad , Ras-related associated with diabetes, is a bona fide target of p53. Overexpression of p53 upregulates the expression of Rad mRNA and protein, besides DNA damage-mediated Rad expression is in a p53-dependent manner. The -2934/-2905 bp Rad promoter region, containing three el-Deiry half-sites, was recognized by p53 and required for p53-mediated Rad gene activation. DNA-damaging agents treatment increased p53 occupancy and histone acetylation in the region of Rad promoter containing the p53- response element. Expression of Rad causes the extension of cell morphology and inhibits the phosphorylation of cofilin, a downstream of Rho signaling, which regulates actin dynamics. The 14-3-3 binding of Rad is essential for its ability to induce dephosphorylation of cofilin. Furthermore, cell migration and invasion were inhibited by Rad, whose deficiency promoted cell invasion and alleviated the p53-mediated invasion suppression.Clinical studies showed that loss of Rad mRNA and protein expression in non-small cell lung carcinoma tissues is significant. Together our results unveil a mechanism that p53 may inhibit cell migration and invasion by interfering actin dynamics via Rad activation, and implicate a tumor suppressor role of Rad in lung cancer.
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