Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1.
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.
Ye
Feng-Chun
FC
Tumor Virology Program, Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Blackbourn
David J
DJ
Mengel
Michael
M
Xie
Jian-Ping
JP
Qian
Li-Wu
LW
Greene
Whitney
W
Yeh
I-Tien
IT
Graham
David
D
Gao
Shou-Jiang
SJ
D042702:Angiopoietin-2 / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000821:virology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006564:Herpesviridae; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008853:Microscopy; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D042702:Angiopoietin-2; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4