Heat Shock Factor-1 and Death Ligand Expression

描述（由申请人提供）：应激途径的激活和凋亡程序的参与代表了细胞对损伤的两种基本反应。细胞应激反应的协调是由热休克因子-1 （HSF-1）的转录活性介导的，HSF-1是热休克蛋白表达的主要调节因子。应激诱导的死亡配体表达调控是细胞凋亡转录调控的一个范例，与免疫系统的稳态调控有关。本研究探讨了热休克因子-1 （HSF-1）在免疫调节中的作用，因为它影响死亡配体的表达。我们将确定(a) HSF-1是否在体内调节FasL表达的诱导及其后果。死亡配体表达改变的生理后果最好的例证是FasL在(i)激活诱导细胞死亡（AICD）和（ii） T淋巴细胞外周缺失中的升高。我们建议利用HSF-1 - / -小鼠和细胞收获从这些动物的角色来确定HSF-1 upregulation FasL的表达和致敏细胞Fas-mediated细胞凋亡与上市有关和外围删除(b)信号通路激活的T细胞受体激活的结果直接影响HSF-1调节死亡配体表达的转录活动和(c)的精确机制HSF-1-mediated转录FasL表达的调控，重点是其与NFAT的相互作用。为此，这一目标将确定HSF-1的非热休克靶点，重要的是，NFAT和HSF-1之间的新型合作相互作用。最终，这一目标将解决HSF-1的转录活性是否代表了一种基本的应激反应机制，通过调节死亡配体的表达来调节细胞对损伤的敏感性。综上所述，我们想提出HSF-1在多种应激源下的普遍激活代表了协调调节多种非热休克靶基因（包括那些密切参与细胞凋亡调节的基因）的基本机制。HSF-1与其他转录因子（其中一个可能是NFAT）的协同相互作用可以根据应激的性质和持续时间，并可能以细胞类型特异性的方式，对基因表达进行差异调节。这些研究将剖析由于T细胞受体激活而产生的信号，这些信号影响HSF-1活性，以调节死亡配体的表达和对凋亡的敏感性，并通过这样做将定义一个涉及T细胞功能和维持免疫稳态的新调控途径。

DESCRIPTION (provided by applicant): Activation of the stress pathway and engagement of the apoptotic program represent two fundamental cellular responses to damage. Coordination of the cellular stress response is mediated by the transcriptional activity of heat shock factor-1 (HSF-1), the primary regulator of heat shock protein expression. Stress-induced regulation of death ligand expression represents a paradigm for the transcriptional regulation of apoptosis with implications in the homeostatic regulation of the immune system. This proposal examines the role of heat shock factor-1 (HSF-1) in immune regulation as a consequence of its effects on the expression of death ligands. We will determine (a) if HSF-1 regulates the induction and consequences of FasL expression in vivo. The physiological consequences of altered death ligand expression are best exemplified by the elevation of FasL in (i) activation induced cell death (AICD) and (ii) peripheral deletion in T lymphocytes. We propose to utilize HSF-1-/- mice and cells harvested from these animals to determine the role of HSF-1 in the upregulation of FasL expression and sensitization of cells to Fas-mediated apoptosis that is associated with AICD and peripheral deletion (b) which of the signaling pathways activated as a consequence of T cell receptor activation impact directly on the transcriptional activity of HSF-1 to modulate death ligand expression and (c) the precise mechanism of HSF-1-mediated transcriptional regulation of FasL expression with emphasis on its interaction with NFAT. To that end, this aim will identify a non-heat shock target for HSF-1 and significantly, a novel cooperative interaction between NFAT and HSF-1. Ultimately, this aim will address if the transcriptional activity of HSF-1 represents a fundamental stress-responsive mechanism engaged to modulate cellular sensitivity to damage via regulation of the expression of the death ligands. In summary, we would like to propose that the ubiquitous activation of HSF-1 in response to multiple stressors represents a fundamental mechanism to coordinately regulate a variety of non-heat shock target genes including those intimately involved in the regulation of apoptosis. Co-operative interaction of HSF-1 with other transcription factors, one of which may be NFAT, could serve to differentially regulate gene expression according to the nature and duration of the stress and potentially in a cell type specific manner. The studies outlined will dissect those signals generated as a consequence of T cell receptor activation that impact on HSF-1 activity to regulate death ligand expression and sensitivity to apoptosis and by doing so will define a novel regulatory pathway involved in T cell function and maintenance of immune homeostasis.