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Molecular and Cellular Biology, April 2007, p. 2713-2731, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.00657-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

p85 Acts as a Novel Signal Transducer for Mediation of Cellular Apoptotic Response to UV Radiation

Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, New York 10987,¹ Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd., Baton Rouge, Louisiana 70808,² The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, Minnesota 55912,³ Department of Microbiology and Immunology, University of Western Ontario, Sibens-Drake Research Institute, 1400 Western Rd., London, Ontario N6G 2V4, Canada⁴

Received 15 April 2006/ Returned for modification 12 June 2006/ Accepted 29 December 2006

Apoptosis is an important cellular response to UV radiation (UVR), but the corresponding mechanisms remain largely unknown. Here we report that the p85 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-) gene expression. This special effect of p85 was unrelated to the PI-3K-dependent signaling pathway. Further evidence demonstrated that the inducible transcription factor NFAT3 was the major downstream target of p85 for the mediation of UVR-induced apoptosis and TNF- gene transcription. p85 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- gene promoter that served as the NFAT3 recognition sequences. Chromatin immunoprecipitation assays further confirmed that the recruitment of NFAT3 to the endogenous TNF- promoter was regulated by p85 upon UVR exposure. Finally, the knockdown of the NFAT3 level by its specific small interfering RNA decreased UVR-induced TNF- gene transcription and cell apoptosis. The knockdown of endogenous p85 blocked NFAT activity and TNF- gene transcription, as well as cell apoptosis. Thus, we demonstrated p85-associated but PI-3K-independent cell death in response to UVR and identified a novel p85/NFAT3/TNF- signaling pathway for the mediation of cellular apoptotic responses under certain stress conditions such as UVR.

Published ahead of print on 22 January 2007.