TY - JOUR
T1 - A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo
AU - Bell, Helen S.
AU - Dufès, Christine
AU - O'Prey, Jim
AU - Crighton, Diane
AU - Bergamaschi, Daniele
AU - Lu, Xin
AU - Schätzlein, Andreas G.
AU - Vousden, Karen H.
AU - Ryan, Kevin
PY - 2007/4/2
Y1 - 2007/4/2
N2 - 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.
AB - 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.
KW - photodynamic therapy
KW - protoporphyrin IX
KW - aminolevulinic acid
KW - apoptosis
KW - gene therapy
KW - cancer
KW - tumors
KW - tumor suppressor p53
KW - pharmacology
KW - cancer therapy
KW - cancer research
UR - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1810568
U2 - 10.1172/JCI28920
DO - 10.1172/JCI28920
M3 - Article
SN - 0021-9738
VL - 117
SP - 1008
EP - 1018
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -