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

Lun Song, Jingxia Li, Jianping Ye, Gang Yu, Jin Ding, Dongyun Zhang, Weiming Ouyang, Zigang Dong, Sung O. Kim, Chuanshu Huang

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Apoptosis is an important cellular response to UV radiation (UVR), but the corresponding mechanisms remain largely unknown. Here we report that the p85α 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-α) gene expression. This special effect of p85α was unrelated to the PI-3K-dependent signaling pathway. Further evidence demonstrated that the inducible transcription factor NFAT3 was the major downstream target of p85α for the mediation of UVR-induced apoptosis and TNF-α gene transcription. p85α 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-α gene promoter that served as the NFAT3 recognition sequences. Chromatin immunoprecipitation assays further confirmed that the recruitment of NFAT3 to the endogenous TNF-α promoter was regulated by p85α upon UVR exposure. Finally, the knockdown of the NFAT3 level by its specific small interfering RNA decreased UVR-induced TNF-α gene transcription and cell apoptosis. The knockdown of endogenous p85α blocked NFAT activity and TNF-α gene transcription, as well as cell apoptosis. Thus, we demonstrated p85α-associated but PI-3K-independent cell death in response to UVR and identified a novel p85α/NFAT3/TNF-α signaling pathway for the mediation of cellular apoptotic responses under certain stress conditions such as UVR.

Original languageEnglish (US)
Pages (from-to)2713-2731
Number of pages19
JournalMolecular and cellular biology
Volume27
Issue number7
DOIs
StatePublished - Apr 1 2007

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    Song, L., Li, J., Ye, J., Yu, G., Ding, J., Zhang, D., Ouyang, W., Dong, Z., Kim, S. O., & Huang, C. (2007). p85α acts as a novel signal transducer for mediation of cellular apoptotic response to UV radiation. Molecular and cellular biology, 27(7), 2713-2731. https://doi.org/10.1128/MCB.00657-06