Heat Shock Factor-1 and Death Ligand Expression

热休克因子 1 和死亡配体表达

• 批准号: 7253413
• 负责人: HELEN MARY BEERE
• 金额: $ 25.03万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253413
• 关键词: Address; Animals; Apoptosis; Apoptotic; Calcium; Cell Death; Cell physiology; Cells; Cellular Stress Response; Cessation of life; Elevation; Event; Fibrinogen; Gene Expression; Gene Targeting; Generations; Genetic Transcription; Harvest; Heat shock proteins; Heat-Shock Response; Homeostasis; Immune; Immune system; Lead; Ligands; Ligation; Maintenance; Mediating; Nature; Nuclear Translocation; Numbers; Pathway interactions; Pattern; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Reactive Oxygen Species; Receptor Activation; Regulation; Regulatory Pathway; Role; Shock; Signal Pathway; Signal Transduction; Stress; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Transcriptional Regulation; Tumor Necrosis Factor Ligand Superfamily Member 6; Up-Regulation; base; biological adaptation to stress; cell type; heat-shock factor 1; immune function; in vivo; mouse HSF1 protein; novel; programs; protein expression; response; stressor; transcription factor

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.

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对损伤的两种基本细胞反应。细胞应激反应的协调由热休克因子-1（HSF-1）的转录活性介导，热休克因子-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节代表了细胞凋亡转录调节的范例，其在免疫系统的稳态调节中具有意义。该建议检查热休克因子-1（HSF-1）在免疫调节中的作用，作为其对死亡配体表达的影响的结果。我们将确定（a）HSF-1是否调节体内FasL表达的诱导和结果。死亡配体表达改变的生理学后果最好通过FasL在（i）活化诱导的细胞死亡（AICD）和（ii）T淋巴细胞中的外周缺失中的升高来例证。我们提出利用HSF-1-/-小鼠和从这些动物收获的细胞来确定HSF-1在上调FasL表达和细胞对Fas介导的凋亡的敏感性中的作用，所述细胞对与AICD和外周缺失相关的Fas介导的凋亡敏感（B），作为T细胞受体活化的结果而活化的信号传导途径直接影响HSF-1的转录活性。1调节死亡配体表达的精确机制和（c）HSF-1介导的FasL表达的转录调节的精确机制，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，并且重要的是，NFAT和HSF-1之间的新型合作相互作用。最终，该目标将解决HSF-1的转录活性是否代表参与通过调节死亡配体的表达来调节细胞对损伤的敏感性的基本应激应答机制。总之，我们想提出，HSF-1在响应多种应激源时的普遍激活代表了协调调节各种非热休克靶基因的基本机制，包括那些密切参与细胞凋亡调节的基因。HSF-1与其他转录因子（其中之一可能是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方式差异调节基因表达。概述的研究将剖析作为T细胞受体活化的结果产生的那些信号，其影响HSF-1活性以调节死亡配体表达和对凋亡的敏感性，并且通过这样做将定义涉及T细胞功能和维持免疫稳态的新的调节途径。