The stability of the p53 tumor suppressor protein is regulated by inte
raction with Mdm2, the product of a p53-inducible gene. Mdm2-targeted
degradation of p53 depends on the interaction between the two proteins
and is mediated hv the proteasome. We show here that in addition to t
he N-terminal Mdm2 binding domain, the C terminus of p53 participates
in the ability of p53 to be degraded by Mdm2. In contrast, alterations
in the central DNA binding domain of p53, which change the conformati
on of the p53 protein, do not abrogate the sensitivity of the protein
to Mdm2-mediated degradation. The importance of the C-terminal oligome
rization domain to Mdm2-targeted degradation of p53 is likely to refle
ct the importance of oligomerization of the full-length p53 protein fo
r interaction with Mdm2, as previously shown in vitro. Interestingly,
the extreme C-terminal region of p53, outside the oligomerization doma
in, was also shown to be necessary for efficient degradation, and dele
tion of this region stabilized the protein without abrogating its abil
ity to bind to Mdm2. Mdm2-resistant p53 mutants were not further stabi
lized following DNA damage, supporting a role for Mdm2 as the principa
l regulator of p53 stability in cells. The extreme C terminus of the p
53 protein has previously been shown to contain several regulatory ele
ments, raising the possibility that either allosteric regulation of p5
3 by this domain or interaction between this region and a third protei
n plays a role in determining the sensitivity of p53 to Mdm2-directed
degradation.