GELDANAMYCIN-STIMULATED DESTABILIZATION OF MUTATED P53 IS MEDIATED BYTHE PROTEASOME IN-VIVO

Mutation of the tumor suppressor gene p53 is the most common genetic a bnormality detected in human cancers, Wild type p53 is a short-lived p rotein with very low basal intracellular levels, Most mutated forms of the protein, however, display markedly increased intracellular levels as an essential feature of their positive transforming activity, In t his report, we have used selective inhibitors of the 20S proteasome to demonstrate that processing of p53 by ubiquitination and proteasome-m ediated degradation is impaired by commonly occurring mutations of the protein, We found that this impairment of p53 turnover can be reverse d by treatment of tumor cells with the benzoquinone ansamycin, geldana mycin, leading to a marked reduction in intracellular p53 levels. Fina lly, using cells which over-express a mutant p53 protein, we were able to demonstrate that restoration of proteasome-mediated degradation by geldanamycin is accompanied by p53 polyubiquitination, Although much remains to be learned about the mechanisms involved, our data demonstr ate that selective de-stabilization of mutant transforming proteins su ch as p53 can be achieved pharmacologically with agents such as geldan amycin which modify the function of molecular chaperone proteins withi n tumor cells.