title: Negative regulation of p53 by Ras superfamily protein RBEL1A.
abstract: We had previously reported that RBEL1A, a novel Ras-like GTPase, was overexpressed in multiple human malignancies and that its depletion suppressed cell growth. However, the underlying molecular mechanism remained to be elucidated. Here we report that depletion of endogenous RBEL1A results in p53 accumulation due to increased p53 half-life whereas increased expression of RBEL1A reduces p53 levels under unstressed and genotoxic stress conditions. RBEL1A directly interacts with p53 and MDM2, and strongly enhances MDM2-dependent p53 ubiquitylation and degradation. We also found that RBEL1A modulation of p53 ubiquitylation by MDM2 does not depend on its GTPase activity. We have also defined the p53 oligomeric domain and RBEL1A GTPase domain to be the crucial regions for p53-RBEL1A interactions. Importantly, we have found that RBEL1A strongly interferes with p53 transactivation function; thus our results indicate that RBEL1A appears to function as a novel p53 negative regulator that facilitates MDM2-dependent p53 ubiquitylation and degradation.
authors.affiliation: Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Ki
authors.initials: K
authors.lastname: Lui
authors.forename: Jie
authors.initials: J
authors.lastname: An
authors.forename: Joanne
authors.initials: J
authors.lastname: Montalbano
authors.forename: Jingxue
authors.initials: J
authors.lastname: Shi
authors.forename: Chad
authors.initials: C
authors.lastname: Corcoran
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Sheikh
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C526916:RABL6 protein, human; D018631:ras Proteins
keywords: GTPase; MDM2; Ubiquitylation, Ras superfamily; p53 tumor suppressor