Hdmx stabilizes Mdm2 and p53

The Mdma protein is a key regulator of p53 activity and stability. Upon bin ding, Mdma inhibits the transcription regulatory activity of p53 and promot es its rapid degradation. In this study we investigated the effect of the h uman Mdm2 homologue Hdmx on p53 stability. We found that Hdmx does not targ et p53 for degradation, although, like Mdm2, it inhibits p53-mediated trans cription activation. On the contrary, Hdmx was found to counteract the degr adation of p53 by Mdma, and to stabilize both p53 and Mdma, The RING finger of Hdmx was found to be necessary and sufficient for this stabilization, a nd it probably involves hetero-oligomerization with the RING finger of Mdm2 , which may lead to inhibition of Mdma's ubiquitin ligase activity. However , Hdmx does not relieve the inhibition by Mdm2 of transcription activation by p53, probably due to the formation of a trimeric complex consisting of H dmx, Mdm2, and p53, We propose a model in which Hdmx secures a pool of larg ely inactive p53, which, upon the induction of stress, can be quickly activ ated.