) The objective of the proposed research is to define the direct contribution of the Epstein-Barr virus (EBV) EBNA-1 protein to EBV-associated lymphoma. Although EBNA-1 indirectly contributes to the tumorigenic potential of EBV through its viral genome maintenance function, several observations support a direct role of EBNA-1 in tumorigenesis. Specifically: i) EBNA-1 is a transcriptional regulator with the potential to target cellular gene expression, a mechanism that would enable EBNA-1 to influence cellular processes important to tumorigenesis; ii) loss of EBNA-1 expression in Akata Burkitt lymphoma (BL) cells is associated with lower tumorigenic potential; and iii) actively expressed EBNA-1 transgenes predispose mice to B-cell tumors. Using BL as a model system, the applicant will address the contribution of EBNA-1 to tumorigenesis focusing on the two defining features of this tumor: EBV infection in which EBNA-1 is the only known viral protein expressed and the deregulated expression of the c-myc proto-oncogene. To fulfill the objective, the applicant proposes three specific aims.
Aim 1 : Determine the tumorigenic potential of EBNA-1 in an EBV-negative BL-cell background; to do this, EBNA-1 will be stably expressed in EBV-negative Akata and other BL cells, and the tumorigenic potential of these cells relative to their EBV-positive and EBV-negative counterparts will be assayed.
Aim 2 : Define direct contributions of EBNA-1 to the oncogenic potential of EBV; specifically, the applicant will determine the role of EBNA-1 in EBV-mediated deregulation of c-myc expression and the ability of EBNA-1 to inhibit c-myc-induced apoptosis. Additionally, he will assess the potential of EBNA-1 to complement c-myc function in co-transformation assays.
Aim 3 : Identify EBNA-1 responsive cellular genes and evaluate their contribution to tumorigenic potential; using an inducible EBNA-1 expression system and representational difference analysis, the applicant will identify cellular genes that are activated or repressed by EBNA-1 and will then delineate the functions of the proteins encoded by these genes with respect to tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073544-03
Application #
2748916
Study Section
Special Emphasis Panel (SRC (C2))
Program Officer
Cremer, Kenneth J
Project Start
1996-09-30
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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