This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, L. Articles by Damania, B. Search for Related Content PubMed PubMed Citation Articles by Wang, L. Articles by Damania, B.

Immortalization of Primary Endothelial Cells by the K1 Protein of Kaposi's Sarcoma–Associated Herpesvirus

Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Requests for reprints: Blossom Damania, Lineberger Comprehensive Cancer Center, University of North Carolina, CB #7295, Chapel Hill, NC 27599. Phone: 919-843-6011; Fax: 425-930-1087; E-mail: damania{at}med.unc.edu.

Kaposi's sarcoma–associated herpesvirus (KSHV) is linked to three different human cancers: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The Kaposi's sarcoma lesion expresses high levels of angiogenic factors and is comprised of a mixed cell population, including endothelial cells that are infected with KSHV. We find that the KSHV K1 protein is expressed in Kaposi's sarcoma lesions and can immortalize and extend the life span of primary human umbilical vein endothelial cells in culture. Vascular endothelial growth factor (VEGF) is critical for the survival of endothelial cells, and we show that expression of K1 in endothelial cells resulted in increased levels of secreted VEGF and the activation of key signaling pathways, including the VEGF/VEGF receptor and the phosphatidylinositol-3'-OH-kinase (PI3K) pathway. The SH2 binding motifs present in the cytoplasmic tail of K1 were critical for K1's ability to activate these pathways. Activation of PI3K by K1 results in activation of Akt kinase and mammalian target of rapamycin and inactivation of the proapoptotic proteins FKHR, glycogen synthase kinase-3, and Bad, which are events indicative of cell survival. Because activation of the PI3K pathway is critical for transformation of many human cells, we suggest that PI3K activation by K1 is involved in endothelial cell immortalization and contributes to KSHV-associated tumorigenesis. We also report that K1 enhances angiogenesis in vivo and increases tumor vasculature and tumor size. (Cancer Res 2006; 66(7): 3658-66)

This article has been cited by other articles:

				Z. Berkova, S. Wang, J. F. Wise, H. Maeng, Y. Ji, and F. Samaniego Mechanism of Fas Signaling Regulation by Human Herpesvirus 8 K1 Oncoprotein J Natl Cancer Inst, March 18, 2009; 101(6): 399 - 411. [Abstract] [Full Text] [PDF]

				V. A. Morris, A. S. Punjabi, and M. Lagunoff Activation of Akt through gp130 Receptor Signaling Is Required for Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphatic Reprogramming of Endothelial Cells J. Virol., September 1, 2008; 82(17): 8771 - 8779. [Abstract] [Full Text] [PDF]

				C. C. Tomlinson and B. Damania Critical Role for Endocytosis in the Regulation of Signaling by the Kaposi's Sarcoma-Associated Herpesvirus K1 Protein J. Virol., July 1, 2008; 82(13): 6514 - 6523. [Abstract] [Full Text] [PDF]

				L. Wang and B. Damania Kaposi's Sarcoma-Associated Herpesvirus Confers a Survival Advantage to Endothelial Cells Cancer Res., June 15, 2008; 68(12): 4640 - 4648. [Abstract] [Full Text] [PDF]

				L. E. Huye, S. Ning, M. Kelliher, and J. S. Pagano Interferon Regulatory Factor 7 Is Activated by a Viral Oncoprotein through RIP-Dependent Ubiquitination Mol. Cell. Biol., April 15, 2007; 27(8): 2910 - 2918. [Abstract] [Full Text] [PDF]

				A. S. Punjabi, P. A. Carroll, L. Chen, and M. Lagunoff Persistent Activation of STAT3 by Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells J. Virol., March 1, 2007; 81(5): 2449 - 2458. [Abstract] [Full Text] [PDF]

				S.-H. Sin, D. Roy, L. Wang, M. R. Staudt, F. D. Fakhari, D. D. Patel, D. Henry, W. J. Harrington Jr, B. A. Damania, and D. P. Dittmer Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling Blood, March 1, 2007; 109(5): 2165 - 2173. [Abstract] [Full Text] [PDF]

				S. Wang, S. Wang, H. Maeng, D. P. Young, O. Prakash, L. E. Fayad, A. Younes, and F. Samaniego K1 protein of human herpesvirus 8 suppresses lymphoma cell Fas-mediated apoptosis Blood, March 1, 2007; 109(5): 2174 - 2182. [Abstract] [Full Text] [PDF]