p19ras interacts with and activates p73 by involving the MDM2 protein

p73beta is a structural and functional homologue of p53, a tumor suppressor gene. In this study, we identified a novel p73beta-binding protein, p19ras, by the yeast two-hybrid screening method. Alternative splicing of the proto-oncogene H-ras pre-mRNA has led to two distinct transcripts, p19ras and p21ras. In both endogenous and overexpressed systems, we confirmed that p19ras binds to full-length p73beta in vivo and in vitro. Coexpression of p19ras with p73beta stimulated the transcriptional activity of p73beta. Ras proteins are known to be small membrane-localized guanine nucleotide-binding proteins. However, unlike other Ras proteins, p19ras is localized in the nucleus and the cytosol and its interaction with p73beta occurred exclusively in the nucleus. Oncogenic MDM2 (mouse double minutes 2) is a known repressor of p73 transcriptional activity. In this study, when p19ras was bound to MDM2, it further inhibited the association of MDM2 to the p73beta protein. In addition, p19ras abolished MDM2-mediated transcriptional repression of p73beta. Therefore, this study presents a novel pathway of Ras signaling that occurs in the nucleus, involving p19ras and p73beta. Furthermore, a p19ras-mediated novel regulatory mechanism of p73 involving the MDM2 protein is described.