INDUCTION OF FAS AND FAS LIGAND EXPRESSION IN T CELLS

描述：(改编自调查者摘要)：激活诱导 细胞死亡(AICD)是维持免疫的基本机制之一 耐受性和淋巴细胞动态平衡。AICD通常通过产生的信号进行 通过Fas(CD95/APO-1)/Fas配体(FasL/CD95L)之间的相互作用， 引发负责执行Caspase的级联激活 以转录不依赖的方式进行的细胞凋亡过程。因此，表达式 Fas和FasL是决定Fas和FasL命运的最后检查点 活化的T淋巴细胞。虽然已经进行了广泛的研究， Fas/FasL诱导的执行机制，我们的研究对 调控Fas和FasL表达的分子机制。我们以前的 研究表明，T细胞杂交瘤的激活导致AICD，一种 这一过程完全依赖于Fas和FasL。早些时候，我们报道了一个关键的 原癌蛋白c-Myc在激活诱导细胞凋亡中的作用 最近确定c-Myc的作用是通过调节FasL发挥作用的 表情。此外，Fas L的表达需要蛋白激酶C的激活和钙离子的共同作用 动员，似乎被限制在细胞周期的G1/M期，并且是 仅受PKC活性调节，可能通过调节TDAG51和P53。 因此，Fas和FasL的表达是由不同的 分子途径。这个应用程序的目标是表征分子 Fas/FasL表达的调控机制。这些实验将检查细胞 FasL表达调控中的周期状态，特别强调 C-Myc和cdc5A在正义和反义转染中的作用。此外, 他们将研究TCR介导的PKC激活过程以及PKC如何 TDAG51和P53是通过调节TDAG51和P53的功能发挥作用的 Fas表达的调控。这些研究将为我们提供新的线索 对免疫系统的分子机制的理解 通过细胞凋亡进行调节。自Fas/FasL介导的细胞死亡以来 与肿瘤免疫、癌症发展、中性粒细胞变性和 随着年龄的增长，Fas/FasL表达调控机制的阐明 使这些疾病能够得到更好的管理和预后。

DESCRIPTION: (Adapted from the Investigator's abstract): 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.