Activation-induced cell death (AICD) is one of the fundamental mechanisms maintaining immune tolerance and lymphocyte homeostasis. AICD often proceeds via signals generated by the interaction between Fas (CD95/APO-1)/Fas ligand (FasL/CD95L), which elicits the activation of a cascade of caspases responsible for executing the apoptosis process in a transcription-independent manner. Thus, the expression of Fas and FasL is on of the final checkpoints determining the fate of activated T lymphocytes. While extensive studies have been conducted on Fas/FasL-induced execution machinery, our research has investigated on the molecular mechanisms regulating the expression of Fas and FasL. Our previous studies have demonstrated that activation of T-cell hybridomas leads to AICD, a process completely dependent on Fas and FasL. Earlier, we reported a crucial role of proto-oncoprotein c-Myc in activation-induced apoptosis; we have recently determined that the effect of c-Myc is exerted through regulating FasL expression. Moreover, Fas L expression requires both PKC activation and Ca++ mobilization, appears to be restricted to G1/M phase of the cell cycle, and is regulated solely by the activity of PKC, probably by regulating TDAG51 and p53. Therefore, the expression of Fas and FasL is strictly controlled by distinct molecular pathways. The goal of this application is to characterize molecular mechanisms regulating Fas/FasL expression. The experiments will examine cell cycle status in the control of FasL expression, with particular emphasis on the role of c-Myc and cdc5A by sense and anti-sense transfections. In addition, they will investigate the process of TCR-mediated PKC activation and how PKC activity is exerted through modulating the function of TDAG51 and p53 in the regulation of Fas expression. These studies will shed new light on the understanding of the molecular mechanisms by which the immune system is regulated through apoptosis. Since Fas/FasL-mediated cell death has been implicated in tumor immunity, cancer development, neutronal degeneration, and aging, the elucidation of the mechanisms regulating Fas/FasL expression will enable better management and prognosis of these diseases.
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