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p38 and STAT3 activation by vGPCR in KSHV-infected cells

Authors Liu M, Guo S

Published 6 September 2010 Volume 2010:2 Pages 103—113


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Mingli Liu, Shanchun Guo

Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

Abstract: The molecular mechanism whereby viral G protein-coupled receptor (vGPCR) signaling regulates vascular endothelial growth factor (VEGF) expression in Kaposi sarcoma (KS) formation remains incompletely defined. mECK36 cells, generated by transfection of mouse bone marrow endothelial cells with Kaposi’s sarcoma-associated herpesviruses (KSHV) bacterial artificial chromosome (KSHVBac36), have been reported to be angiogenic, tumorigenic, and suitable for demonstrating a nonredundant role for vGPCR in KSHV-mediated tumorigenesis.1 In this report we used mECK36 and the cells composed of wild-type KSHVBac36 or the cells without vGPCR, namely vGPCR-null KSHVBac36 mutant, to dissect the molecular mechanisms of VEGF secretion induced by vGPCR in the context of KSHV infection. We found that vGPCR activates VEGF transcription via p38 MAPK and STAT3 in mECK36 and mECK36-derived cell models. We also found that in cells containing KSHV genome, STAT3 is tyrosine-phosphorylated and translocated into the nucleus, transactivating the target VEGF gene by binding to the specific DNA element TT (N4–5) AA in a strictly vGPCR-dependent manner. Moreover, treatment of mECK36-derived cells with AG490 or a dominant negative STAT3 DNA vector showed strong inhibitory effects on vGPCR-induced VEGF promoter activity. In addition, vGPCR can upregulate STAT3 mRNA levels. Taken together, our findings show that vGPCR plays a nonredundant role in STAT3 activation in KSHV infected cells and that this activation plays an important role in the connection of the viral oncogene vGPCR and VEGF upregulation. Our results indicate the broad signaling activating capacity of vGPCR in the context of KSHV infection and suggest that the STAT3 pathway could be targeted for preventing KSHV-mediated angiogenesis in KS.

Kaposi’s sarcoma, vGPCR, p38, STAT3, KSHV

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