Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain

A synthetic 22-mer peptide (peptide 46) derived from the p53 C-terminal dom ain can restore the growth suppressor function of mutant p53 proteins in hu man tumor cells (G. Selivanova et al., Nat. Med. 3:632-638, 1997). Here we demonstrate that peptide 46 binds mutant p53. Peptide 46 binding sites were found within both the core and C-terminal domains of p53. Lys residues wit hin the peptide were critical for both p53 activation and core domain bindi ng. The sequence-specific DNA binding of isolated tumor-derived mutant p53 core domains was restored by a C-terminal polypeptide. Our results indicate that C-terminal peptide binding to the core domain activates p53 through d isplacement of the negative regulatory C-terminal domain. Furthermore, stab ilization of the core domain structure and/or establishment of novel DNA co ntacts may contribute to the reactivation of mutant p53. These findings sho uld facilitate the design of p53-reactivating drugs for cancer therapy.