INDUCTION OF FAS AND FAS LIGAND EXPRESSION IN T CELLS

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.