NFAT and CREB regulate Kaposi's sarcoma-associated herpesvirus-induced cyclooxygenase 2 (COX-2)
| Autor: | Bala Chandran, Neelam Sharma-Walia, Arun George Paul, Waseem Ahmad, Karthic Chandran, Kinjan Patel |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Gene Expression Regulation
Viral Transcription Genetic Immunology Response element Blotting Western Fluorescent Antibody Technique Electrophoretic Mobility Shift Assay Enzyme-Linked Immunosorbent Assay Biology CREB medicine.disease_cause Transfection Microbiology Dinoprostone Immunoenzyme Techniques Virology medicine Transcriptional regulation Humans RNA Messenger Kaposi's sarcoma-associated herpesvirus Phosphorylation Protein kinase A Cyclic AMP Response Element-Binding Protein Luciferases Promoter Regions Genetic Transcription factor Cells Cultured Cell Nucleus NFATC Transcription Factors Reverse Transcriptase Polymerase Chain Reaction NFAT Dermis Herpesviridae Infections Fibroblasts Molecular biology Cyclic AMP-Dependent Protein Kinases Cell biology Virus-Cell Interactions Cyclooxygenase 2 Insect Science DNA Viral Herpesvirus 8 Human biology.protein Endothelium Vascular Signal Transduction |
| Zdroj: | Journal of virology. 84(24) |
| ISSN: | 1098-5514 |
| Popis: | COX-2 has been implicated in Kaposi's sarcoma-associated herpesvirus (KSHV) latency and pathogenesis (A. George Paul, N. Sharma-Walia, N. Kerur, C. White, and B. Chandran, Cancer Res. 70:3697-3708, 2010; P. P. Naranatt, H. H. Krishnan, S. R. Svojanovsky, C. Bloomer, S. Mathur, and B. Chandran, Cancer Res. 64:72-84, 2004; N. Sharma-Walia, A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog. 6:e1000777, 2010; N. Sharma-Walia, H. Raghu, S. Sadagopan, R. Sivakumar, M. V. Veettil, P. P. Naranatt, M. M. Smith, and B. Chandran, J. Virol. 80:6534-6552, 2006). However, the precise regulatory mechanisms involved in COX-2 induction during KSHV infection have never been explored. Here, we identified cis -acting elements involved in the transcriptional regulation of COX-2 upon KSHV de novo infection. Promoter analysis using human COX-2 promoter deletion and mutation reporter constructs revealed that nuclear factor of activated T cells (NFAT) and the cyclic AMP (cAMP) response element (CRE) modulate KSHV-mediated transcriptional regulation of COX-2. Along with multiple KSHV-induced signaling pathways, infection-induced prostaglandin E 2 (PGE 2 ) also augmented COX-2 transcription. Infection of endothelial cells markedly induced COX-2 expression via a cyclosporine A-sensitive, calcineurin/NFAT-dependent pathway. KSHV infection increased intracellular cAMP levels and activated protein kinase A (PKA), which phosphorylated the CRE-binding protein (CREB) at serine 133, which probably led to interaction with CRE in the COX-2 promoter, thereby enhancing COX-2 transcription. PKA selective inhibitor H-89 pretreatment strongly inhibited CREB serine 133, indicating the involvement of a cAMP-PKA-CREB-CRE loop in COX-2 transcriptional regulation. In contrast to phosphatidylinositol 3-kinase and protein kinase C, inhibition of FAK and Src effectively reduced KSHV infection-induced COX-2 transcription and protein levels. Collectively, our study indicates that mediation of COX-2 transcription upon KSHV infection is a paradigm of a complex regulatory milieu involving the interplay of multiple signal cascades and transcription factors. Intervention at each step of COX-2/PGE 2 induction can be used as a potential therapeutic target to treat KSHV-associated neoplasm and control inflammatory sequels of KSHV infection. |
| Databáze: | OpenAIRE |
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