p85α acts as a novel signal transducer for mediation of cellular apoptotic response to UV radiation

被引:37
作者
Song, Lun
Li, Jingxia
Ye, Jianping
Yu, Gang
Ding, Jin
Zhang, Dongyun
Ouyang, Weiming
Dong, Zigang
Kim, Sung O.
Huang, Chuanshu
机构
[1] NYU, Sch Med, Nelson Inst Environm Med, Tuxedo Pk, NY 10987 USA
[2] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA
[3] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA
[4] Univ Western Ontario, Sibens Drake Res Inst, Dept Microbiol & Immunol, London, ON N6G 2V4, Canada
关键词
D O I
10.1128/MCB.00657-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Apoptosis is an important cellular response to UV radiation (UVR), but the corresponding mechanisms remain largely unknown. Here we report that the p85 alpha regulatory subunit of phosphatidylinositol 3-kinase (PI-3K) exerted a proapoptotic role in response to UVR through the induction of tumor necrosis factor alpha (TNF-alpha) gene expression. This special effect of p85a was unrelated to the PI-3K-dependent signaling pathway. Further evidence demonstrated that the inducible transcription factor NFAT3 was the major downstream target of p85a for the mediation of UVR-induced apoptosis and TNF-alpha gene transcription. p85a regulated UVR-induced NFAT3 activation by modulation of its nuclear translocation and DNA binding and the relevant transcriptional activities. Gel shift assays and site-directed mutagenesis allowed the identification of two regions in the TNF-a gene promoter that served as the NFAT3 recognition sequences. Chromatin immuno-precipitation assays further confirmed that the recruitment of NFAT3 to the endogenous TNF-alpha promoter was regulated by p85a upon UVR exposure. Finally, the knockdown of the NFAT3 level by its specific small interfering RNA decreased UVR-induced TNF-a gene transcription and cell apoptosis. The knockdown of endogenous p85a blocked NFAT activity and TNF-a gene transcription, as well as cell apoptosis. Thus, we demonstrated p85 alpha-associated but PI-3K-independent cell death in response to UVR and identified a novel p85 alpha/NFAT3/TNF-alpha signaling pathway for the mediation of cellular apoptotic responses under certain stress conditions such as UVR.
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收藏
页码:2713 / 2731
页数:19
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