A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo
Helen S. Bell, … , Karen H. Vousden, Kevin M. Ryan
Helen S. Bell, … , Karen H. Vousden, Kevin M. Ryan
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):1008-1018. https://doi.org/10.1172/JCI28920.
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Research Article Oncology

A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo

Abstract

The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP — a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.

Authors

Helen S. Bell, Christine Dufes, Jim O’Prey, Diane Crighton, Daniele Bergamaschi, Xin Lu, Andreas G. Schätzlein, Karen H. Vousden, Kevin M. Ryan

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Figure 1

The p53-derived peptide 37AA induces cell death without direct activation of p53 target genes.

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The p53-derived peptide 37AA induces cell death without direct activatio...
(A) Representation of the p53 mutants used in this study. Full-length p53 is shown in green with 5 evolutionarily conserved regions (boxes) shown in yellow. Two truncations, tr105 (aa 1–105) and tr210 (aa 1–210), are shown as well as the composition of the 37AA peptide, with aa from conserved box II (residues 118–142) in red and those from conserved box III (residues 171–181) in blue. (B–E) Cells were transiently transfected with the indicated plasmids and subsequently analyzed 36 hours (C and E) and 48 hours later (D) for changes in cell cycle and cell death by flow cytometry. Ap, apoptosis. (B) Cells were transiently transfected with the indicated plasmids, and transgene expression was determined by Western blotting. The additional lower band seen following expression of 37AA represents expression from an alternate internal methionine. Mutation of this methionine to alanine resulted in expression of the larger protein species only and produced identical results (not shown). (F) No direct activation of p53 target genes by 37AA was observed. Saos-2 cells were transfected with luciferase reporter plasmids for the p53 target genes p21, Bax, and PIG3 as well as with the indicated expression constructs. After 24 hours, cells were assayed for luciferase activity, and the data were normalized against transfected β-gal activity. Values represent fold activation relative to activity of GFP alone, which was assigned as 1.