title: 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, 155 Li-Nong St., Taipei 112, Taiwan.
authors.forename: Bo-Yuan
authors.initials: BY
authors.lastname: Hsiao
authors.forename: Chun-Chin
authors.initials: CC
authors.lastname: Chen
authors.forename: Pei-Chen
authors.initials: PC
authors.lastname: Hsieh
authors.forename: Tsun-Kai
authors.initials: TK
authors.lastname: Chang
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Yeh
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Wu
authors.forename: Han-Shui
authors.initials: HS
authors.lastname: Hsu
authors.forename: Fung-Fang
authors.initials: FF
authors.lastname: Wang
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; C084355:RRAD protein, human; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins