Epstein-Barr virus (EBV) causes infectious mononucleosis in adolescents and malignant B lymphocyte proliferation in AIDS patients and patients undergoing immune suppression for organ transplantation. EBV is etiologically associated with African Burkitt's lymphoma and nasopharyngeal carcinoma. In vitro, EBV transformed, latently infected B lymphocytes contain EBV episomes and express nine virus-encoded proteins. Six are nuclear proteins (EBNAs) and three are the integral membrane proteins, LMP1, LMP2A, and LMP2B. These nine proteins are presumed to mediate latent virus infection or B lymphocyte proliferation and thus are under intense investigation. LMP2A is the most consistently detected protein in B lymphocytes from normal individuals with EBV latent infections and along with EBNA1 and LMP1 are consistently detected in EBV-associated malignancies. Our previous studies have shown that LMP2A is essential for down modulation of cell surface receptor mediated signal transduction in B lymphocytes infected with EBV. By down modulating cell surface signal transduction, LMP2A is important for maintaining EBV latent infection in vitro. We have shown that LMP2A functional mimics a B cell receptor by associating with the Syk protein tyrosine kinase (PTK) and the Src family PTKs. LMP2A associates with Nedd4-family ubiquitin ligases resulting in the ubiquitination of LMP2A-associated Lyn and Syk PTKs. The elucidation of LMP2A function in in vitro latent infection utilizing biochemical and genetic techniques will be the focus of this research proposal. An understanding of LMP2A function may provide insight for the development of novel therapeutics for the treatment of EBV-related malignancies in AIDS patients as well as immunocompetent individuals harboring EBV latent infections. The following aims are proposed: 1) Investigate LMP2A targeting to lipid rafts and the role of lipid raft constituents in LMP2A function. 2) Investigate trafficking of LMP2A and LMP2A-associated proteins. 3) Investigate the importance of ubiquitination and role of Nedd4-family ubiqutin ligases in LMP2A function. 4) Investigate the properties of LCLs transformed and latently infected with the LMP2A mutant viruses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA062234-11S1
Application #
6917391
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Rosenfeld, Bobby
Project Start
1993-12-15
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
11
Fiscal Year
2004
Total Cost
$6,683
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Swanson-Mungerson, Michelle; Bultema, Rebecca; Longnecker, Richard (2010) Epstein-Barr virus LMP2A imposes sensitivity to apoptosis. J Gen Virol 91:2197-202
Bultema, R; Longnecker, R; Swanson-Mungerson, M (2009) Epstein-Barr virus LMP2A accelerates MYC-induced lymphomagenesis. Oncogene 28:1471-6
Ikeda, Masato; Longnecker, Richard (2009) The c-Cbl proto-oncoprotein downregulates EBV LMP2A signaling. Virology 385:183-91
Anderson, Leah J; Longnecker, Richard (2009) Epstein-Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo. Blood 113:108-16
Anderson, Leah J; Longnecker, Richard (2008) EBV LMP2A provides a surrogate pre-B cell receptor signal through constitutive activation of the ERK/MAPK pathway. J Gen Virol 89:1563-8
Rovedo, Mark; Longnecker, Richard (2008) Epstein-Barr virus latent membrane protein 2A preferentially signals through the Src family kinase Lyn. J Virol 82:8520-8
Anderson, Leah J; Longnecker, Richard (2008) An auto-regulatory loop for EBV LMP2A involves activation of Notch. Virology 371:257-66
Omerovic, Jasmina; Longnecker, Richard (2007) Functional homology of gHs and gLs from EBV-related gamma-herpesviruses for EBV-induced membrane fusion. Virology 365:157-65
Swanson-Mungerson, Michelle; Longnecker, Richard (2007) Epstein-Barr virus latent membrane protein 2A and autoimmunity. Trends Immunol 28:213-8
Ikeda, Masato; Longnecker, Richard (2007) Cholesterol is critical for Epstein-Barr virus latent membrane protein 2A trafficking and protein stability. Virology 360:461-8

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