title: Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain.
abstract: A synthetic 22-mer peptide (peptide 46) derived from the p53 C-terminal domain can restore the growth suppressor function of mutant p53 proteins in human 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 within the peptide were critical for both p53 activation and core domain binding. 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 displacement of the negative regulatory C-terminal domain. Furthermore, stabilization of the core domain structure and/or establishment of novel DNA contacts may contribute to the reactivation of mutant p53. These findings should facilitate the design of p53-reactivating drugs for cancer therapy.
authors: Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden.
authors: G
authors: G
authors: Selivanova
authors: L
authors: L
authors: Ryabchenko
authors: E
authors: E
authors: Jansson
authors: V
authors: V
authors: Iotsova
authors: K G
authors: KG
authors: Wiman
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D013489:Suppression, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53