文章基本信息

标题：Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide
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作者：Natalia Issaeva ; Assaf Friedler ; Przemyslaw Bozko 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：23
页码：13303-13307
DOI：10.1073/pnas.1835733100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 Fl-CDB3 (fluorescent derivative of CDB3). Before treatment, the mutant p53 in the cell was predominantly denatured. Fl-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. Fl-CDB3 sensitized cancer cells that carried wild-type p53 to p53-dependent {gamma}-radiation-induced apoptosis. Although Fl-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.