title: p85alpha acts as a novel signal transducer for mediation of cellular apoptotic response to UV radiation.
abstract: Apoptosis is an important cellular response to UV radiation (UVR), but the corresponding mechanisms remain largely unknown. Here we report that the p85alpha 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 p85alpha was unrelated to the PI-3K-dependent signaling pathway. Further evidence demonstrated that the inducible transcription factor NFAT3 was the major downstream target of p85alpha for the mediation of UVR-induced apoptosis and TNF-alpha gene transcription. p85alpha 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-alpha gene promoter that served as the NFAT3 recognition sequences. Chromatin immunoprecipitation assays further confirmed that the recruitment of NFAT3 to the endogenous TNF-alpha promoter was regulated by p85alpha upon UVR exposure. Finally, the knockdown of the NFAT3 level by its specific small interfering RNA decreased UVR-induced TNF-alpha gene transcription and cell apoptosis. The knockdown of endogenous p85alpha blocked NFAT activity and TNF-alpha gene transcription, as well as cell apoptosis. Thus, we demonstrated p85alpha-associated but PI-3K-independent cell death in response to UVR and identified a novel p85alpha/NFAT3/TNF-alpha signaling pathway for the mediation of cellular apoptotic responses under certain stress conditions such as UVR.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Lun
authors.initials: L
authors.lastname: Song
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Jianping
authors.initials: J
authors.lastname: Ye
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: Sung O
authors.initials: SO
authors.lastname: Kim
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D050778:NFATC Transcription Factors / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D050778:NFATC Transcription Factors; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases