Sodium orthovanadate inhibits p53-mediated apoptosis.
Sodium orthovanadate (vanadate) inhibits the DNA-binding activity of p53, but its precise effects on p53 function have not been examined. Here, we show that vanadate exerts a potent antiapoptotic activity through both transcription-dependent and transcription-independent mechanisms relative to other p53 inhibitors, including pifithrin (PFT) alpha. We compared the effects of vanadate to PFTalpha and PFTmicro, an inhibitor of transcription-independent apoptosis by p53. Vanadate suppressed p53-associated apoptotic events at the mitochondria, including the loss of mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and the interaction of p53 with Bcl-2. Similarly, vanadate suppressed the apoptosis-inducing activity of a mitochondrially targeted temperature-sensitive p53 in stable transfectants of SaOS-2 cells. In radioprotection assays, which rely on p53, vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Together, our findings indicated that vanadate effectively suppresses p53-mediated apoptosis by both transcription-dependent and transcription-independent pathways, and suggested that both pathways must be inhibited to completely block p53-mediated apoptosis.
Morita
Akinori
A
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan. morita@rs.noda.tus.ac.jp
Yamamoto
Shinichi
S
Wang
Bing
B
Tanaka
Kaoru
K
Suzuki
Norio
N
Aoki
Shin
S
Ito
Azusa
A
Nanao
Tomohisa
T
Ohya
Soichiro
S
Yoshino
Minako
M
Zhu
Jin
J
Enomoto
Atsushi
A
Matsumoto
Yoshihisa
Y
Funatsu
Osamu
O
Hosoi
Yoshio
Y
Ikekita
Masahiko
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008813:Mice, Inbred ICR; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects*; D014638:Vanadates / Q000494:pharmacology*
C545747:2-phenylacetylenesulfonamide; D052160:Benzothiazoles; D011837:Radiation-Protective Agents; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D014638:Vanadates; C121565:pifithrin