Rescue of mutant p53 transcription function by ellipticine.

The p53 tumor suppressor is frequently inactivated in tumors by point mutations in the DNA-binding domain, resulting in loss of sequence-specific DNA binding and transcription function. We present evidence that ellipticine can restore the transactivation function of several transfected p53 mutants (175 H, 248W, 249S, 273 H, 281G), resulting in the induction of p53-responsive genes (p21(WAF1),MDM2) and activation of a p53-responsive luciferase reporter. Ellipticine also activates mutant p53 function in tumor cells expressing endogenous 194F, 233L, 241F, and 273C mutants. Treatment with ellipticine alters mutant p53 reactivity to conformation-sensitive Pab1620 and Pab240 antibodies and increases its sequence-specific DNA-binding activity in vivo. Finally, ellipticine activates mutant p53 and induces p21(WAF1) and MDM2 expression in nude mouse tumor xenografts. These results demonstrate that ellipticine can restore transcription function to mutant p53. This property may contribute to the selectivity of ellipticine-derived compounds against tumor cell lines expressing mutant p53.