Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2.

Abstract	Oncoprotein Mdm2 is a master negative regulator of the tumor suppressor p53 and has been recently shown to regulate the ubiquitination of beta-arrestin 2, an important adapter and scaffold in signaling of G-protein-coupled receptors (GPCRs). However, whether beta-arrestin 2 has any effect on the function of Mdm2 is still unclear. Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination. Further experiments revealed that overexpression of beta-arrestin 2 enhanced the p53-mediated apoptosis while suppression of endogenous beta-arrestin 2 expression by RNA interference technology considerably attenuated the p53-mediated apoptosis. Our study thus suggests that beta-arrestin 2 may serve as a cross-talk linker between GPCR and p53 signaling pathways.
Authors	Ping Wang, Hua Gao, Yanxiang Ni, Beibei Wang, Yalan Wu, Lili Ji, Linhua Qin, Lan Ma, Gang Pei
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 8 Pg. 6363-70 (Feb 21 2003) ISSN: 0021-9258 [Print] United States
PMID	12488444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	ARRB2 protein, human Arrb2 protein, mouse Arrestins DNA, Complementary Nuclear Proteins Proto-Oncogene Proteins Receptors, Cell Surface Recombinant Proteins Tumor Suppressor Protein p53 Ubiquitin beta-Arrestin 2 beta-Arrestins MDM2 protein, human Mdm2 protein, mouse Proto-Oncogene Proteins c-mdm2 GTP-Binding Proteins
Topics	Animals Apoptosis (physiology) Arrestins (physiology) Brain (embryology, physiology) Cell Line DNA, Complementary GTP-Binding Proteins (physiology) Gene Expression Regulation Gene Library Humans Kidney Mice Nuclear Proteins Proto-Oncogene Proteins (genetics, physiology) Proto-Oncogene Proteins c-mdm2 Receptors, Cell Surface (physiology) Recombinant Proteins (metabolism) Transfection Tumor Suppressor Protein p53 (metabolism) Ubiquitin (metabolism) beta-Arrestin 2 beta-Arrestins

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