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 the most frequently detected genetic event in human cancers. We examined whether 9-hydroxyellipticine (9HE), a cytotoxic agent, affected the tertiary structure of mutant p53 and DNA binding characteristics. Although several types of p53 mutants were resistant to degradation by calpain, the p53 mutants treated with 9HE were markedly sensitive to calpain as well as wild-type p53. Furthermore, mutant p53 proteins isolated from 9HE-treated cells regained the ability to bind a wild-type-specific p53 DNA consensus sequence. Wild-type p53 proteins prepared from both untreated and 9HE-treated cells bound the p53 consensus sequence and were degradaded by calpain equally well. These results suggest that 9HE affects the tertiary structure of mutated p53, which results in the restoration of DNA binding characteristics.
Sugikawa
E
E
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Tsunoda
S
S
Nakanishi
N
N
Ohashi
M
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002154:Calpain / Q000494:pharmacology; D016384:Consensus Sequence; D004247:DNA / Q000378:metabolism*; D004611:Ellipticines / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation / Q000187:drug effects; D012474:Salmon; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D004611:Ellipticines; D016159:Tumor Suppressor Protein p53; D004247:DNA; C008009:9-hydroxyellipticine; D002154:Calpain