Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV infection is a leading cause of lymphomas especially in immunocompromised individuals and has been associated with nasopharyngeal carcinoma (NPC) and gastric carcinoma. EBV transforms primary B cells in vitro and EBV latent membrane protein 1 (LMP-1) is required for the process. LMP-1 induces the expression of IRF-7 and activates IRF-7 protein by phosphorylation and nuclear translocation. Activated IRF-7 then exerts its effect on target genes. However, little is known about the role of IRF-7 in the pathogenesis of EBV-associated diseases. Our data suggests that both expression and activation of IRF-7 are associated with EBV transformation process in vitro, and IRF-7 is highly expressed and activated in EBV-associated human central nervous system lymphoma (CNS lymphoma) in vivo. IRF-7 by itself has oncogenic potential, but it also has a cooperative effect with LMP-1 in transforming rodent cells. Furthermore, reduction of IRF-7 in EBV-transformed STAT-1-null B cells reduced the number of live cells at low serum conditions. Therefore, we hypothesize that IRF-7 may be a factor in EBV-mediated transformation process. In the proposed work, we will study in Aim 1 the mechanism of IRF-7 to transform rodent cells. Transformation domain(s) in IRF-7 will be determined.
In Aim 2, we will study the mechanism of cooperative transformation between IRF-7 and LMP-1. We will examine if LMP-1-mediated nuclear translocation of IRF-7 is related to the cooperative transformation.
In Aim 3, the role of IRF-7 in EBV transformation process will be determined by introducing small interfering RNA of IRF-7 or dominant negative mutant for IRF-7 transformation into EBV-transformed cells. This study should provide an insight of how IRF-7 participates in EBV transformation, and expand our knowledge about IRFs as well as the pathogenesis of EBV-associated CNS lymphoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108951-04
Application #
7369791
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Daschner, Phillip J
Project Start
2005-04-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$217,299
Indirect Cost
Name
University of Nebraska Lincoln
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588
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Valente, Robert M; Ehlers, Erica; Xu, Dongsheng et al. (2012) Toll-like receptor 7 stimulates the expression of Epstein-Barr virus latent membrane protein 1. PLoS One 7:e43317
Xu, Dongsheng; Meyer, Florencia; Ehlers, Erica et al. (2011) Interferon regulatory factor 4 (IRF-4) targets IRF-5 to regulate Epstein-Barr virus transformation. J Biol Chem 286:18261-7
Ahmad, Humera; Gubbels, Rachel; Ehlers, Erica et al. (2011) Kaposi sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF). J Biol Chem 286:7865-72
Xu, Dongsheng; Zhang, Luwen (2010) Viral transformation for production of personalized type I interferons. Biotechnol J 5:578-81
Zhao, Yong; Xu, Dongsheng; Jiang, Yanjun et al. (2010) Dual functions of interferon regulatory factors 7C in Epstein-Barr virus-mediated transformation of human B lymphocytes. PLoS One 5:e9459
Jiang, Yanjun; Xu, Dongsheng; Zhao, Yong et al. (2008) Mutual inhibition between Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus lytic replication initiators in dually-infected primary effusion lymphoma. PLoS One 3:e1569
Xu, Dongsheng; Zhao, Lingjun; Del Valle, Luis et al. (2008) Interferon regulatory factor 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes. J Virol 82:6251-8
Papugani, Anil; Coleman, Tricia; Jones, Clinton et al. (2008) The interaction between KSHV RTA and cellular RBP-Jkappa and their subsequent DNA binding are not sufficient for activation of RBP-Jkappa. Virus Res 131:1-7
Xu, Dongsheng; Coleman, Tricia; Zhang, Jun et al. (2007) Epstein-Barr virus inhibits Kaposi's sarcoma-associated herpesvirus lytic replication in primary effusion lymphomas. J Virol 81:6068-78

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