Latent infection by the Epstein Barr virus (EBV) has been implicated as a causative factor in the development of Burkitts lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and immunodeficiency associated lymphoproliferative disease. The exact mechanisms involved in transformation remain a mystery, however. The applicant has identified a novel B-cell surface receptor whose expression in markedly increased following EBV immortalization of B lymphocytes and in EBV-infected Burkitts lymphomas. TACI (for Transmembrane Activator and CAML Interactor) was isolated by a yeast two- hybrid screen with the intracellular Ca2+ regulating protein CAML as bait. As predicted, crosslinking the TACI receptor activates the NF-AT (Ca2+dependent) transcription factor. Surprisingly, TACI also potently activates API and NF-kB transcription factors following stimulation. TACI appears to be a new member of the family of Tumor Necrosis Factor Receptors (TNFR), which include TNFR, FAS, CD40, and other receptors implicated in initiating growth and programmed cell death in lymphocytes. An attractive hypothesis is that TACI contributes to the transformation of B cells through its activation of multiple transcription factors following EBV infection. The goals of this project are to elucidate the mechanisms of action of TACI in normal and EBV-associated Burkitt lymphoma cells, and to determine its contribution to cellular transformation. Experiments will focus on determining the mechanism of action of TACI by identifying its functional domains, and identifying both extracellular and intracellular protein contacts that mediate its action. Additionally, targeted disruption of the TACI gene in mice will allow the identification of its normal role in regulation of the immune system. Lastly, the proposed project will explore the possibility that experimental manipulation of TACI signaling activating in tumor cells may provide new means to inhibit growth or accelerate death of cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076274-03
Application #
6124433
Study Section
Pathology B Study Section (PTHB)
Program Officer
Wong, May
Project Start
1997-12-16
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
3
Fiscal Year
2000
Total Cost
$237,995
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Mantchev, George T; Cortesao, Catarina S; Rebrovich, Michelle et al. (2007) TACI is required for efficient plasma cell differentiation in response to T-independent type 2 antigens. J Immunol 179:2282-8
Bischof, Daniela; Elsawa, Sherine F; Mantchev, George et al. (2006) Selective activation of TACI by syndecan-2. Blood 107:3235-42
Diaz-de-Durana, Yaiza; Mantchev, George T; Bram, Richard J et al. (2006) TACI-BLyS signaling via B-cell-dendritic cell cooperation is required for naive CD8+ T-cell priming in vivo. Blood 107:594-601
O'Connor, Brian P; Raman, Vanitha S; Erickson, Loren D et al. (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199:91-8
von Bulow, G U; van Deursen, J M; Bram, R J (2001) Regulation of the T-independent humoral response by TACI. Immunity 14:573-82
von Bulow, G U; Russell, H; Copeland, N G et al. (2000) Molecular cloning and functional characterization of murine transmembrane activator and CAML interactor (TACI) with chromosomal localization in human and mouse. Mamm Genome 11:628-32