TACI AND B CELL FUNCTION AND TRANSFORMATION

Project: Research project

Project Details

Description

(adapted from the investigator's abstract) 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

ASJC

  • Medicine(all)