TACI AND B CELL FUNCTION AND TRANSFORMATION

Project: Research project

Description

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.
StatusFinished
Effective start/end date12/16/976/30/08

Funding

  • National Institutes of Health: $252,487.00
  • National Institutes of Health
  • National Institutes of Health: $260,257.00
  • National Institutes of Health: $231,062.00
  • National Institutes of Health: $274,480.00
  • National Institutes of Health: $274,480.00
  • National Institutes of Health: $274,480.00
  • National Institutes of Health: $268,030.00
  • National Institutes of Health: $237,995.00
  • National Institutes of Health: $245,135.00

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Burkitt Lymphoma
B-Lymphocytes
Human Herpesvirus 4
Tumor Necrosis Factor Receptors
Epstein-Barr Virus Infections
Cell Death
Transcription Factors
Growth
NF-kappa B
Cell Surface Receptors
Neoplasms
Hodgkin Disease
Proteins
Immune System
Lymphocytes
Yeasts
Genes
Homeostasis
B-Cell Activation Factor Receptor
B-Cell Activating Factor

ASJC

  • Medicine(all)