Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide

Natalia Issaeva, Assaf Friedler, Przemyslaw Bozko, Klas G. Wiman, Alan R. Fersht*, Galina Selivanova

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

We designed a series of nine-residue peptides that bound to a defined site on the tumor suppressor p53 and stabilized it against denaturation. To test whether the peptides could act as chaperones and rescue the tumor-suppressing function of oncogenic mutants of p53 in living cells, we treated human tumor cells with the fluorescein-labeled peptide FI-CDB3 (fluorescent derivative of CDB3). Before treatment, the mutant p53 in the cell was predominantly denatured. FI-CDB3 was taken up into the cytoplasm and nucleus and induced a substantial up-regulation of wild-type p53 protein and representative mutants. The mutants, His-273 and His-175 p53, adopted the active conformation, with a dramatic decrease in the fraction of denatured protein. In all cases, there was p53-dependent induction of expression of the p53 target genes mdm2, gadd45, and p21, accompanied by p53-dependent partial restoration of apoptosis. FI-CD83 sensitized cancer cells that carried wild-type p53 to p53-dependent γ-radiation-induced apoptosis. Although FI-CDB3 did not elicit a full biological response, it did bind to and rescue p53 in cells and so can serve as a lead for the development of novel drugs for anticancer therapy.

Original languageAmerican English
Pages (from-to)13303-13307
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number23
DOIs
StatePublished - 11 Nov 2003
Externally publishedYes

Fingerprint

Dive into the research topics of 'Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide'. Together they form a unique fingerprint.

Cite this