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Molecular and Cellular Biology, May 1999, p. 3395-3402, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Reactivation of Mutant p53 through Interaction of a C-Terminal Peptide with the Core Domain

Galina Selivanova,* Ludmila Ryabchenko, Emmelie Jansson,dagger Violetta Iotsova,Dagger and Klas G. Wiman*

Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden

Received 10 August 1998/Returned for modification 6 November 1998/Accepted 21 January 1999

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.

* Corresponding author. Mailing address: Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden. Phone: 46 8 7286736. Fax: 46 8 330498. E-mail for Galina Selivanova: Galina.Selivanova{at}mtc.ki.se. E-mail for Klas G. Wiman: Klas.Wiman{at}mtc.ki.se.

dagger Present address: Center for Genome Research, Karolinska Institute, S-171 77 Stockholm, Sweden.

Dagger Present address: Department of Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.

Molecular and Cellular Biology, May 1999, p. 3395-3402, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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