Thymidine phosphorylase inhibits the expression of proapoptotic protein BNIP3.
An angiogenic factor, thymidine phosphorylase (TP), confers resistance to apoptosis induced by hypoxia. We investigated the molecular basis for the suppressive effect of TP on hypoxia-induced apoptosis using Jurkat cells transfected with TP cDNA, Jurkat/TP, and a mock transfectant, Jurkat/CV. TP and 2-deoxy-d-ribose, a degradation product of thymidine generated by TP enzymatic activity, suppressed hypoxia-induced apoptosis. They also inhibited the upregulation of hypoxia-inducible factor (HIF) 1alpha and the proapoptotic factor, BNIP3, and caspase 3 activation induced by hypoxia. Introduction of siRNA against BNIP3 in Jurkat cells decreased the proportion of apoptotic cells under hypoxic condition. These findings suggest that the suppression of BNIP3 expression by TP prevents, at least in part, hypoxia-induced apoptosis. Expression levels of TP are elevated in many malignant solid tumors and thus 2-deoxy-d-ribose generated by TP in these tumors might play an important role in tumor progression by preventing hypoxia-induced apoptosis.
Ikeda
Ryuji
R
Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Tajitsu
Yusuke
Y
Iwashita
Ken-Ichi
K
Che
Xiao-Fang
XF
Yoshida
Kenichi
K
Ushiyama
Mina
M
Furukawa
Tatsuhiko
T
Komatsu
Masaharu
M
Yamaguchi
Tatsuya
T
Shibayama
Yoshihiko
Y
Yamamoto
Masatatsu
M
Zhao
Hong-Ye
HY
Arima
Junko
J
Takeda
Yasuo
Y
Akiyama
Shin-Ichi
S
Yamada
Katsushi
K
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D003855:Deoxyribose / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C090121:BNIP3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D003855:Deoxyribose; D013939:Thymidine Phosphorylase; D053148:Caspase 3; D053181:Caspase 8