) Epstein-Barr virus is one of a limited number of viruses associated with human cancers and has a high degree of association with one of the three largest groups of AIDS-related malignancies. The ability of EBV to transform primary B lymphocytes is likely to play a role in the development of these malignancies. The objective is to determine the cellular pathways targeted by one of the six viral proteins demonstrated to be essential for transformation, EBNA-3A, that the applicant s preliminary evidence suggests functions as a transcription factor. Specifically, the applicant proposes to: 1) Identify the function of EBNA-3A associated proteins. Preliminary data demonstrates that EBNA-3A associates with at least two cellular proteins, one of which is the J-kappa transcription factor. The unknown EBNA-3A-associated protein(s) will be identified using the yeast two-hybrid system. 2) Identify cellular genes regulated by EBNA-3A. The preliminary data, as well as homology to other viral proteins, suggests that EBNA-3A is highly likely to function as a transcriptional regulator, affecting expression of cellular genes that contribute to EBV-mediated transformation. EBNA-3A-regulated genes will be identified by representational difference analysis. 3) Determine the significance of EBNA-3A function within the context of viral infection. Lastly, the applicant will determine the significance of those EBNA-3A functions that have already been identified, as well as those to be identified in this application, by generating recombinant EBV encoding EBNA-3A with mutations affecting each individual function. By examining the ability of these recombinant EBV genomes to immortalize primary human B lymphocytes, the applicant will determine whether a given function contributes to EBV-mediated transformation. Identification of EBNA-3A-associated proteins and EBNA-3A regulated genes will enable determination of the cellular pathways targeted by EBNA-3A. Analysis of these pathways, using EBNA-3A as a probe, is highly likely to not only further the understanding of EBV- associated malignancies, but also increase the knowledge of the control of cellular proliferation that may be disrupted in other types of cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073561-05
Application #
6172881
Study Section
Special Emphasis Panel (SRC (C2))
Program Officer
Wong, May
Project Start
1996-09-30
Project End
2003-07-31
Budget Start
2000-08-01
Budget End
2003-07-31
Support Year
5
Fiscal Year
2000
Total Cost
$235,519
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105