The protein p53 suppresses tumor development by potently inducing tumor cell death, making it an obvious target for anticancer therapeutics. However, this therapeutic approach is confounded by the fact that genetic mutations cause loss or inactivation of p53 in approximately 50% of human cancers. As the p53-related protein p73, which can also induce tumor cell death, is rarely mutated in human cancers, researchers from the Beatson Institute for Cancer Research, United Kingdom, hypothesized that it might represent a more viable target than p53 for the development of broadly applicable anticancer therapeutics.
In the study, which appears online on March 8 in advance of publication in the April print issue of the Journal of Clinical Investigation, Kevin Ryan and colleagues show that a peptide of 37 amino acids in length, which they generated from human p53 (termed 37AA), killed both p53-sufficient and p53-deficient human tumor cell lines. 37AA mediated tumor cell death by binding to the negative regulator of p53-family proteins iASPP and preventing it from repressing the death-inducing function of p73. Furthermore, systemic administration of 37AA to mice with established tumors of human origin (both p53-sufficient and p53-deficient tumors) induced tumor regression in a p73-dependent manner. These data suggest that targeting the p73-mediated pathway of tumor cell death might provide a new avenue of research for the development of anticancer therapeutics.
TITLE: A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo
AUTHOR CONTACT:
Kevin M. Ryan
Beatson Institute for Cancer Research, Glasgow, United Kingdom.
Phone: +44-1413303655; Fax: +44-1419426521; E-mail: k.ryan@beatson.gla.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28920
Journal
Journal of Clinical Investigation