Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma, primary effusion lymphoma, and plasmablastic multicentric Castleman's disease. STAT3 has been shown to be important for the maintenance of primary effusion lymphoma cells in culture and is chronically activated in many tumor cell lines. However, little is known about the role of KSHV in the activation of STAT3 or the role of STAT3 in KS tumors. We demonstrate that STAT3 is activated by KSHV infection of endothelial cells, the KS tumor cell type, in a biphasic fashion. Viral binding and entry activate STAT3 in the first 2 h after infection, but this activation dissipates by 4 h postinfection. By 12 h after KSHV infection, concomitant with the expression of latent genes, STAT3 is once again activated, and this activation persists for as long as latent infection is maintained. Activated STAT3 translocates to the nucleus, where it can bind to STAT3-specific DNA elements and can activate STAT3-dependent promoter activity. Conditioned medium from KSHV-infected endothelial cells is able to transiently activate STAT3, indicating the involvement of a secreted factor and that a latency-associated factor in KSHV-infected cells is necessary for sustained activation. KSHV upregulates gp130 receptor expression, and both gp130 and JAK2 are required for the activation of STAT3. However, neither human nor viral interleukin-6 is required for STAT3 activation. Persistent activation of the oncogenic signal transducer, STAT3, by KSHV may play a critical role in the viral pathogenesis of Kaposi's sarcoma, as well as in primary effusion lymphomas.
Punjabi
Almira S
AS
Department of Microbiology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
Carroll
Patrick A
PA
Chen
Lei
L
Lagunoff
Michael
M
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000821:virology*; D017353:Gene Deletion; D005814:Genes, Viral; D006566:Herpesviridae Infections / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D053614:Janus Kinase 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014764:Viral Proteins / Q000235:genetics
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014764:Viral Proteins; C120140:interleukin-6, RRV-HHV-8; D050822:Cytokine Receptor gp130; D004247:DNA; C507924:JAK2 protein, human; D053614:Janus Kinase 2