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Journal of Virology, April 2007, p. 3980-3991, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02089-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Promotes Angiogenesis by Inducing Angiopoietin-2 Expression via AP-1 and Ets1{triangledown}

Feng-Chun Ye,1,2 David J. Blackbourn,8 Michael Mengel,9 Jian-Ping Xie,1,2 Li-Wu Qian,1,2 Whitney Greene,1,2 I-Tien Yeh,5 David Graham,8 and Shou-Jiang Gao1,2,3,4,6,7*

Tumor Virology Program, Children's Cancer Research Institute,1 Departments of Pediatrics,2 Microbiology and Immunology,3 Molecular Medicine,4 Pathology,5 San Antonio Cancer Institute, The University of Texas Health Science Center, San Antonio, Texas,6 Tumor Virology Group, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China,7 Cancer Research United Kingdom Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom,8 Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany9

Received 25 September 2006/ Accepted 24 January 2007

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is required for the development of Kaposi's sarcoma (KS), a highly inflammatory angiogenic tumor of endothelial cells commonly found in untreated AIDS patients. Angiopoietin 2 (Ang-2) modulates the vasculature during inflammation and angiogenesis, but the mechanism by which KSHV regulates Ang-2 expression has not been investigated. Here, we show that KSHV infection of primary human umbilical vein endothelial cells induced the expression and release of Ang-2, which in turn was required for KSHV-induced paracrine-dependent angiogenesis in vivo. Ang-2 was strongly expressed in small vessels and spindle tumor cells in KS tumors. Mechanistically, KSHV activated the Ang-2 promoter via AP-1 and Ets1 transcriptional factors, which were mediated by ERK, JNK, and p38 mitogen-activated protein kinase (MAPK) pathways. Our findings demonstrate the importance of Ang-2 in KS angiogenesis and define a novel role for AP-1 and MAPK pathways in regulating angiogenesis. This study also illustrates a distinct mechanism by which a tumor virus modulates vasculature to promote tumorigenesis and exemplifies the convergence of oncogenesis and angiogenesis pathways in tumor development.

* Corresponding author. Mailing address: Tumor Virology Program, Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229. Phone: (210) 562-9030. Fax: (210) 562-9014. E-mail: gaos{at}uthscsa.edu

{triangledown} Published ahead of print on 7 February 2007.

Journal of Virology, April 2007, p. 3980-3991, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02089-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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