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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2903-2911. Prepublished online as a Blood First Edition Paper on July 1, 2004; DOI 10.1182/blood-2003-12-4436. This Article Full Text (PDF) All Versions of this Article: 2003-12-4436v1 104/9/2903    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Montaner, S. Articles by Gutkind, J S Search for Related Content PubMed PubMed Citation Articles by Montaner, S. Articles by Gutkind, J S Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 31, 2003 Accepted June 16, 2004 The small GTPase Rac1 links the Kaposi's sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia Silvia Montaner, Akrit Sodhi, Joan-Marc Servitja, Amanda K Ramsdell, Ana Barac, Earl T Sawai, and J S Gutkind* Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA Department of Medical Pathology and Comparative Pathology Graduate Group, University of California at Davis, Davis, CA, USA * Corresponding author; email: sg39v{at}nih.gov. Kaposi's sarcoma (KS) is a multifocal angioproliferative neoplasm strictly dependent on angiogenic growth factors and cytokines and invariably associated with infection by the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8). A G protein-coupled receptor encoded by KSHV (vGPCR) is able to initiate KS-like tumors when targeted to the vascular endothelium of mice. Analogous to human KS, vGPCR sarcomagenesis involves the paracrine secretion of angiogenic growth factors and pro-inflammatory molecules from vGPCR-expressing cells. Here we demonstrate that vGPCR upregulates expression and secretion of critical KS cytokines by stimulating key transcription factors, including NFB, AP-1, and NFAT, through the activation of the small G protein Rac1. Inhibition of Rac1 blocked vGPCR-induced transcription and secretion of KS cytokines, including IL-6, IL-8 and GRO, in vitro, and reduced vGPCR tumorigenesis in vivo. Moreover, endothelial-specific infection with the constitutively-active Rac1 QL induced vascular lesions in mice that were remarkably similar to early vGPCR experimental lesions. These results identify Rac1 as a key mediator of vGPCR paracrine neoplasia, suggesting that this small G protein and its downstream effectors may represent suitable therapeutic targets for the treatment of KS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Q. Ma, L. E. Cavallin, B. Yan, S. Zhu, E. M. Duran, H. Wang, L. P. Hale, C. Dong, E. Cesarman, E. A. Mesri, et al. Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma PNAS, May 26, 2009; 106(21): 8683 - 8688. [Abstract] [Full Text] [PDF] S. Efklidou, R. Bailey, N. Field, M. Noursadeghi, and M. K. Collins vFLIP from KSHV inhibits anoikis of primary endothelial cells J. Cell Sci., February 15, 2008; 121(4): 450 - 457. [Abstract] [Full Text] [PDF] M. J. Martin, T. Tanos, A. B. Garcia, D. Martin, J. S. Gutkind, O. A. Coso, and M. J. Marinissen The G{alpha}12/13 Family of Heterotrimeric G Proteins and the Small GTPase RhoA Link the Kaposi Sarcoma-associated Herpes Virus G Protein-coupled Receptor to Heme Oxygenase-1 Expression and Tumorigenesis J. Biol. Chem., November 23, 2007; 282(47): 34510 - 34524. [Abstract] [Full Text] [PDF] P. Depeille, J. J. Young, E. A. Boguslawski, B. D. Berghuis, E. J. Kort, J. H. Resau, A. E. Frankel, and N. S. Duesbery Anthrax Lethal Toxin Inhibits Growth of and Vascular Endothelial Growth Factor Release from Endothelial Cells Expressing the Human Herpes Virus 8 Viral G Protein Coupled Receptor Clin. Cancer Res., October 1, 2007; 13(19): 5926 - 5934. [Abstract] [Full Text] [PDF] W. Tan, D. Martin, and J. S. Gutkind The G{alpha}13-Rho Signaling Axis Is Required for SDF-1-induced Migration through CXCR4 J. Biol. Chem., December 22, 2006; 281(51): 39542 - 39549. [Abstract] [Full Text] [PDF] S. A. R. Rezaee, C. Cunningham, A. J. Davison, and D. J. 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