p19(ras) interacts with and activates p73 by involving the MDM2 protein

Abstract

p73 beta is a structural and functional homologue of p53, a tumor suppressor gene. In this study, we identified a novel p73 beta-binding protein, p19(ras), by the yeast two-hybrid screening method. Alternative splicing of the proto-oncogene H-ras pre-mRNA has led to two distinct transcripts, p19(ras) and p21(ras). In both endogenous and overexpressed systems, we confirmed that p19(ras) binds to full-length p73 beta in vivo and in vitro. Coexpression of p19(ras) with p73 beta stimulated the transcriptional activity of p73 beta. Ras proteins are known to be small membrane-localized guanine nucleotide-binding proteins. However, unlike other Ras proteins, p19(ras) is localized in the nucleus and the cytosol and its interaction with p73 beta occurred exclusively in the nucleus. Oncogenic MDM2 ( mouse double minutes 2) is a known repressor of p73 transcriptional activity. In this study, when p19(ras) was bound to MDM2, it further inhibited the association of MDM2 to the p73 beta protein. In addition, p19(ras) abolished MDM2-mediated transcriptional repression of p73 beta. Therefore, this study presents a novel pathway of Ras signaling that occurs in the nucleus, involving p19(ras) and p73 beta. Furthermore, a p19(ras)-mediated novel regulatory mechanism of p73 involving the MDM2 protein is described.