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Journal of Virology, March 2001, p. 2929-2937, Vol. 75, No. 6
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.6.2929-2937.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Linkage between STAT Regulation and Epstein-Barr
Virus Gene Expression in Tumors
Honglin
Chen,1
Jae Myun
Lee,1
Yongsheng
Zong,2
Michael
Borowitz,3
Mun Hon
Ng,4
Richard F.
Ambinder,1 and
S.
Diane
Hayward1,*
Oncology Center1 and
Department of Pathology,3 Johns Hopkins
School of Medicine, Baltimore, Maryland 21231; Sun Yat-Sen
University of Medical Sciences, Guangzhou, People's Republic of
China2; and Department of
Microbiology, The University of Hong Kong, Hong Kong4
Received 23 August 2000/Accepted 22 December 2000
Epstein-Barr virus (EBV) latency gene expression in lymphoblastoid
cell lines is regulated by EBNA2. However, the factors regulating viral
expression in EBV-associated tumors that do not express EBNA2 are
poorly understood. In EBV-associated tumors, EBNA1 and frequently LMP1
are synthesized. We found that an alternative latent membrane protein 1 (LMP1) promoter, L1-TR, located within the terminal repeats is active
in both nasopharyngeal carcinoma and Hodgkin's disease tissues.
Examination of the L1-TR and the standard ED-L1 LMP1 promoters in
electrophoretic mobility shift assays revealed that both promoters
contain functional STAT binding sites. Further, both LMP1 promoters
responded in reporter assays to activation of JAK-STAT signaling.
Cotransfection of JAK1 or v-Src or treatment of cells with the cytokine
interleukin-6 upregulated expression from ED-L1 and L1-TR reporter
plasmids. Cotransfection of a dominant negative STAT3
revealed that
STAT3 is likely to be the biologically relevant STAT for EBNA1 Qp and
LMP1 L1-TR promoter regulation. In contrast, LMP1 expression from ED-L1
was not abrogated by STAT3
, indicating that the two LMP1 promoters are regulated by different STAT family members. Taken together with the
previous demonstration of JAK-STAT activation of Qp driven EBNA1
expression, this places two of the EBV genes most commonly expressed in
tumors under the control of the same signal transduction pathway.
Immunohistochemical analyses of nasopharyngeal carcinoma tumors
revealed that STAT3, STAT5, and STAT1 are constitutively activated in
these tumors while STAT3 is constitutively activated in the malignant
cells of Hodgkin's disease. We hypothesize that chronic or aberrant
STAT activation may be both a necessary and predisposing event for
EBV-driven tumorigenesis in immunocompetent individuals.
*
Corresponding author. Mailing address: Oncology Center,
Johns Hopkins School of Medicine, 1650 Orleans St., Baltimore, MD 21231. Phone: (410) 955-2548. Fax: (410) 502-6802. E-mail:
dhayward{at}jhmi.edu.
Journal of Virology, March 2001, p. 2929-2937, Vol. 75, No. 6
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.6.2929-2937.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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