title: Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation.
abstract: Ral GTPases are critical effectors of Ras, yet the molecular mechanism by which they induce malignant transformation is not well understood. In this study, we found the expression of K-Ras, RalB, and sometimes RalA, but not AKT1/2 and c-Raf, to be required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild-type p53. Down-regulation of K-Ras, RalB, and sometimes RalA increases p53 protein levels and results in a p53-dependent up-regulation of the expression of p21(WAF). K-Ras, RalA, and RalB depletion increases p53 stability as demonstrated by ataxia telangiectasia-mutated kinase activation, increased Ser-15 phosphorylation, and a significant (up to 6-fold) increase in p53 half-life. Furthermore, depletion of K-Ras and RalB inhibits anchorage-independent growth and invasion and interferes with cell cycle progression in a p53-dependent manner. Depletion of RalA inhibits invasion in a p53-dependent manner. Thus, expression of K-Ras and RalB and possibly RalA proteins is critical for maintaining low levels of p53, and down-regulation of these GTPases reactivates p53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation.
authors.affiliation: From the Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute and the Departments of Oncologic Sciences and Molecular Medicine, University of South Florida, Tampa, Florida 33612.
authors.forename: Awet
authors.initials: A
authors.lastname: Tecleab
authors.affiliation: From the Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute and.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute and the Departments of Oncologic Sciences and Molecular Medicine, University of South Florida, Tampa, Florida 33612 said.sebti@moffitt.org.
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; C483163:Ralb protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D012694:Serine; D020169:Caspases; C492198:RALA protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020725:ral GTP-Binding Proteins
keywords: Apoptosis; Cancer Biology; K-Ras; RalA; RalB; Ras Protein; Serine 15 Phosphorylation; Signal Transduction; p53