Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53.
We previously reported that p42/SETbeta is a substrate for caspase-7 in irradiated MOLT-4 cells, and that treating the cells with sodium orthovanadate (vanadate) inhibits p42/SETbeta's caspase-mediated cleavage. Here, we initially found that the inhibitory effect of vanadate was due to the suppression of caspase activation but not of caspase activity. Further investigations revealed that vanadate suppressed upstream of apoptotic events, such as the loss of mitochondrial membrane potential, the conformational change of Bax, and p53 transactivation, although the accumulation, total phosphorylation, and phosphorylation of six individual sites of p53 were not affected. Importantly, vanadate suppressed p53-dependent apoptosis, but not p53-independent apoptosis. Finally, gel-shift and chromatin immunoprecipitation assays conclusively demonstrated that vanadate inhibits the DNA-binding activity of p53. Vanadate is conventionally used as an inhibitor of protein tyrosine phosphatases (PTPs); however, we recommend that the influence of vanadate not only on PTPs but also on p53 be considered before using it.
Morita
A
A
Department of Radiological Health, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan. morita@m.u-tokyo.ac.jp
Zhu
J
J
Suzuki
N
N
Enomoto
A
A
Matsumoto
Y
Y
Tomita
M
M
Suzuki
T
T
Ohtomo
K
K
Hosoi
Y
Y
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D014638:Vanadates / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000737:chemistry
D061945:Caspase Inhibitors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D014638:Vanadates; D020169:Caspases