Proposed model for stabilization of mutant p53 in cancer cells.
Our data suggests that the pro-oncogenic, gain-of-function phenotype of mutant p53 is governed by HSP70 and MDM2 levels. Recurrent interaction of HSP70 with the p53 polypeptide, in an ATP dependent manner, causes transient exposure of its aggregate prone domain(s). Subsequent aggregation of mutant p53 is further augmented by the MDM2-p53 allosteric interaction. This dynamic, irreversible molecular process can sequester other tumour suppressors, such as p73, thus inhibiting their activity. Pro-oncogenic activities of mutant p53 can be manifested through other, non-sequestration based mechanisms as depicted (described previously ). We cannot exclude the possibility that molecular chaperones, including HSP70, are also involved in these processes.