9-hydroxyellipticine alters the conformation and DNA binding characteristics of mutated p53 protein

The tumor suppressor protein p53 is a phosphoprotein which shows growth and transformation suppression functions. Mutational loss of p53 function is t he most frequently detected genetic event in human cancers. We examined whe ther 9-hydroxyellipticine (9HE), a cytotoxic agent, affected the tertiary s tructure of mutant p53 and DNA binding characteristics. Although several ty pes of p53 mutants were resistant to degradation by calpain, the p53 mutant s treated with 9HE were markedly sensitive to calpain as well as wild-type p53. Furthermore, mutant p53 proteins isolated from 9HE-treated cells regai ned the ability to bind a wild-type-specific p53 DNA consensus sequence. Wi ld-type p53 proteins prepared from both untreated and 9HE-treated cells bou nd the p53 consensus sequence and were degradaded by calpain equally well. These results suggest that 9HE affects the tertiary structure of mutated p5 3, which results in the restoration of DNA binding characteristics.