Geldanamycin selectively destabilizes and conformationally alters mutated p53.
Mutated p53 proteins interfere in the function of wild type p53 and may also serve as a dominant oncogene. The vast majority of p53 mutations result in a protein of altered conformation and prolonged half-life. We sought to examine whether geldanamycin, a drug capable of destabilizing several oncogene and proto-oncogene products, could alter the stability and DNA binding characteristics of several mutated p53 proteins. Brief exposure to GA destabilized the p53 protein of several breast, prostate and leukemic cell lines harboring mutated p53 alleles, resulting in a significant reduction in p53 steady state level and half-life. In contrast to its effects on mutated p53, GA altered neither steady state level nor inducibility of the wild type protein. In addition to its effects on protein stability, GA also altered the conformation of mutated p53, so that it was no longer detectable with a mutant conformation-specific antibody. Finally, mutated p53 protein isolated from GA-treated cells regained partial ability to bind a wild type-specific p53 DNA consensus sequence. These data indicate the feasibility of pharmacologic intervention for altering the mutated p53 phenotype.
Blagosklonny
M V
MV
Clinical Pharmacology Branch, NCI, NIH, Bethesda, Maryland 20892, USA.
Toretsky
J
J
Neckers
L
L
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D006207:Half-Life; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic; D009154:Mutation; D011487:Protein Conformation; D000090063:Proto-Oncogene Mas; D011809:Quinones / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011809:Quinones; D016159:Tumor Suppressor Protein p53; D004247:DNA; C001277:geldanamycin