β-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 β-arrestin 2, an important adapter and scaffold in signaling of G-protein-coupled receptors (GPCRs). However, whether β-arrestin 2 has any effect on the function of Mdm2 is still unclear. Our current results demonstrated that the binding of Mdm2 to β-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, β-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of β-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 β-arrestin 2 enhanced the p53-mediated apoptosis while suppression of endogenous β-arrestin 2 expression by RNA interference technology considerably attenuated the p53-mediated apoptosis. Our study thus suggests that β-arrestin 2 may serve as a cross-talk linker between GPCR and p53 signaling pathways.