The contribution of the acidic domain of MDM2 to p53 and MDM2 stability

p53 and MDM2 are both degraded by the ubiquitin-proteasome pathway, MDM2 bi nds p53 and promotes its rapid degradation, MDM2 is an E3 ligase that activ ates self and p53 ubiquitylation, Moreover, MDM2 nuclear-cytoplasmic shuttl ing contributes to p53 degradation in the cytoplasm, We have identified a n ew region of MDM2 which regulates the stability of both p53 and MDM2, The f irst 50 amino-acids of the MDM2 acidic domain (222-272) contribute to MDM2 and MDM2-mediated p53 degradation by a mechanism which is independent of ei ther MDM2 E3-ligase activity or MDM2 nucleo-cytoplasmic shuttling, The tran scriptional coactivator p300 could have been involved, since it binds to th e MDM2 acidic domain, Howe, er, we found that p300 stabilises MDM2, even in absence of an intact acidic domain, indicating that the MDM2 acidic region contributes to proteolysis independently of p300, We propose that the MDM2 acidic domain is required for unbiquitylated MDM2 and p53 to be degraded b y cytoplasmic proteasomes.