INDUCTION OF FAS AND FAS LIGAND EXPRESSION IN T CELLS

Project Details

Description

DESCRIPTION (Adapted from the Investigator's abstract): Activation-
induced cell death (AICD) in T-cells plays a critical role in immune
tolerance and lymphocyte homeostasis. AICD often proceeds via cell death
signals generated from Fas/Fas L interactions, which elicit the activation
of a cascade of proteases in a transcription-independent manner. The
expression of Fas and FasL is thus the final checkpoint determining the
fate of activated T lymphocytes. While there have been extensive studies
on Fas/FasL-induced execution machineries conducted in other laboratories,
the investigator's main research interest is on the molecular mechanisms
for the regulation of Fas and FasL expression. Previous results from the
investigator have shown that activation of T-cell hybridomas leads to
AICD, a process which completely depends on Fas and FasL. Subsequent to
their previous report of the requirement for proto-oncoprotein c-myc in
activation-induced apoptosis, they have found that the effect of c-myc is
exerted through the regulation of FasL expression. The expression of FasL
requires both PKC activation and calcium influx and appears to be
restricted to the G2/M phase of the cell cycle modulated by the activity
of c-myc and cdc25A. In contrast, Fas expression is independent of cell
cycle, and is regulated by the activity of PKC alone, probably by
regulating p53 and TDAG51. The investigator hypothesizes that the
expression of Fas and FasL is strictly controlled at the transcriptional
level, and tightly regulated by distinct molecular pathways. Cell cycle
regulators including the c-myc-cdc25A pathways regulate FasL expression,
while PKC-TDAG51-p53 cascade maintains the Fas expression. The long-term
goals of this study are to characterize molecular mechanisms for the
regulation of Fas/FasL expression. The investigator proposes to further
examine cell cycle status in the control of FasL expression, with
particular emphasis on the role of c-myc and cdc25A, and to investigate
the p53 in the regulation of Fas expression. This could provide a better
understanding of the regulation of the immune system. Since Fas/FasL
mediated cell death has also been implicated in tumor immunity, neuronal
degeneration, and AIDS, elucidation of the mechanisms regulating Fas/FasL
expression could have implication in management and prognosis of these
diseases.
StatusFinished
Effective start/end date7/1/986/30/05

Funding

  • National Institute of Allergy and Infectious Diseases: $197,482.00

ASJC

  • Genetics
  • Molecular Biology
  • Cell Biology

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