Rad is a p53 direct transcriptional target that inhibits cell migration and is frequently silenced in lung carcinoma cells

Abstract

The p53 tumor suppressor exerts its function mainly as a transcriptional activator. Here we show that the Ras-related small GTPase Rad, an inhibitor of Rho kinase, is a direct transcriptional target of p53. Expression of Rad messenger RNA (mRNA) and protein was induced by DNA damage in a p53-dependent manner. The -2934/-2905-bp Rad promoter region, to which p53 bound, was required for p53-mediated Rad gene activation. Treatment by DNA damaging agents increased p53 occupancy and histone acetylation in the region of Rad promoter containing the p53-binding site. Expression of Rad diminished the inhibitory phosphorylation at Ser3 of cofilin, a regulator of actin dynamics, and suppressed migration and invasiveness of cancer cells. Knockdown of Rad promoted cell migration and alleviated the p53-mediated migration suppression. Frequent loss of Rad mRNA and protein expression was observed in non-small cell lung carcinoma tissues. Together our results reveal a mechanism that p53 may inhibit cell migration by disrupting actin dynamics via Rad activation and implicate a tumor suppressor role of Rad in lung cancer.

Ras-induced Epigenetic Inactivation of the RRAD (Ras-related Associated with Diabetes) Gene Promotes Glucose Uptake in a Human Ovarian Cancer Model

“…The fact that the Ras mutation is found only in a certain subset of ovarian cancers (53) and ϳ30% of other human cancers (1, 2) suggested that Ras mutation was not the only cause for RRAD epigenetic inactivation in cancer. Indeed, Hsiao et al recently demonstrated that RRAD was a direct transcriptional target of p53 and that activation of p53 leads to up-regulation of RRAD (25). Considering the fact that p53 is frequently mutated in cancer cells, we speculate that loss of p53 function is another cause for RRAD down-regulation in tumor tissues.…”

“…6, D-F). Considering that RRAD inhibited cell migration in vascular smooth muscle cells (51) and lung cancers (25) and that disruption of RRAD resulted in cell cycle arrest and senescence (20,52), we propose that RRAD is a tumor suppressor gene, which may be a potential new anti-tumor target through regulating RRAD activity.…”

The Rho kinase inhibitor fasudil is involved in p53-mediated apoptosis in human hepatocellular carcinoma cells

“…Bax activation occurs in response to a variety of apoptotic stimuli, and the p53 directly regulates Bax expression and induces apoptosis via the mitochondrial pathway. Rad, a Rho kinase inhibitor, suppressed p53-mediated cell migration in lung cancer [40]. Rho A and ROCK activation is associated with cell migration due to the mutation or loss of p53 [41,42].…”

Long noncoding RNA GIHCG promotes hepatocellular carcinoma progression through epigenetically regulating miR-200b/a/429

“…As important epigenetic modification manners, histone methylation and DNA methylation directly regulate numerous cancer-related genes expression [20][21][22][23]. Aberrant histone methylation and DNA methylation, mediated by histone methyltransferase and DNA methyltransferase, respectively, have been found in many types of cancers [24,25].…”