The role of alpha-helical structure in p53 peptides as a determinant for their mechanism of cell death: necrosis versus apoptosis.
Peptides derived from the N-terminal and C-terminal regions of the p53 tumor suppressor protein, linked to the membrane transduction domain of Antennapedia, have both been found to have significant cytotoxic effects selectively in human cancer cells. However, the N-terminal and C-terminal p53 peptides apparently display very different mechanisms for their anticancer effects. These differential effects can be attributed to dissimilar abilities to form distinctive 3-dimensional structures in extracellular-matrix-like aqueous solution that enable unique and selective cancer cell membrane penetration and effect. N-terminally based p53 peptides, with their ability to form distinctive S-shaped helix-loop-helix structures, are able to rapidly disrupt cancer cell membranes via toroidal-like pore formation causing necrosis; conversely, C-terminally based p53 peptides, due to their more random coil configuration, can be transduced across cancer cell membranes and bind to its intracellular target to cause a Fas pathway mechanism of apoptosis.
Rosal
Ramon
R
Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 701 West 168th Street rm. 5-531, New York, NY 10032, USA.
Brandt-Rauf
Paul
P
Pincus
Matthew R
MR
Wang
Hsin
H
Mao
Yuehua
Y
Li
Yin
Y
Fine
Robert L
RL
D017209:Apoptosis; D016923:Cell Death; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009336:Necrosis / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D010455:Peptides; D016159:Tumor Suppressor Protein p53