Regulation and interplay of Heat Shock Factors in growth-associated proteotoxic stresses

生长相关蛋白毒性应激中热休克因子的调节和相互作用

• 批准号: 10693802
• 负责人: Marc Mendillo
• 金额: $ 32.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693802
• 关键词: Acute; Arginine; Binding; Biochemical; Biological Assay; Biological Models; Cancer Cell Growth; Cell Adhesion; Cell Proliferation; Cell physiology; Cells; Cellular Assay; Chromatin; Complex; Cytoprotection; DNA Binding; Data; Development; Disease; Disparate; Experimental Genetics; Feedback; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Screening; Genetic Transcription; Genomics; Glucose; Goals; Growth; Health; Health Promotion; Heat Stress Disorders; Heat shock factor; Heat shock proteins; Heat-Shock Proteins 70; Heat-Shock Proteins 90; Heat-Shock Response; Heat-Shock Transcription Factor 2; Human; In Vitro; Ischemia; Knowledge; Link; Logic; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator; Metabolic stress; Metabolism; Methods; Modeling; Molecular Chaperones; Mutation; Mutation Analysis; Nerve Degeneration; Neurodegenerative Disorders; Organism; Physiological; Physiology; Process; Proliferating; Proteins; Proteome; Proteomics; Regulation; Reperfusion Injury; Reporter; Role; Series; Site; Source; Stress; Technology; Temperature; Testing; Therapeutic Intervention; Transcriptional Regulation; Viral Cancer; Virus Diseases; biochemical model; biological adaptation to stress; cancer cell; cell growth; chromatin remodeling; cofactor; coping; demethylation; disorder prevention; endoplasmic reticulum stress; genetic regulatory protein; heat shock transcription factor; heat-shock factor 1; human disease; in vivo; novel; paralogous gene; physiologic stressor; prevent; programs; promote resilience; protein folding; protein function; protein structure; proteostasis; proteotoxicity; recruit; response; stress resilience; therapeutic development; tumor; tumor microenvironment

Protein homeostasis (proteostasis), or the proper folding and function of the proteome, is vital for cellular and organismal health. Critical to proteostasis is an evolutionarily ancient cytoprotective mechanism originally characterized in cells subjected to elevated temperatures. This mechanism, termed the Heat Shock Response (HSR), is now known to protect against many diverse sources of proteotoxic stress. A hallmark of the HSR is the profound transcriptional induction of molecular chaperones known as heat shock proteins (HSPs), a process regulated by the transcription factor Heat Shock Factor 1 (HSF1). Because this rapid and robust transcriptional induction can be provoked by simply increasing temperature, the HSR has been used as a model system in the gene expression field for decades. As such, the processes that govern HSF1 activation and transcriptional regulation upon heat shock have been extensively studied. However, evidence accumulating over the last decade has revealed a more complicated picture of HSF1 function. We have found that in cancer, HSF1 directly regulates the transcription of genes involved in cellular processes which extend far beyond protein folding, in a manner distinct from the classic HSR. This has been mirrored in studies of HSF1 in other physiological contexts, such as in the tumor microenvironment and in organismal development. The mechanisms which enable HSF1's regulatory plasticity, and the underlying logic that connects the disparate set of HSF1-regulated genes with HSF1's role in proteostasis, is not well understood. Here we propose to use cancer as a as a model system to study the mechanisms that underlie HSF1's non-canonical regulatory roles. Through a series of unbiased proteomic and genetic screens we identify a factor critical for HSF1 in this distinct physiological context, and a surprising multifaceted role for a non-canonical HSF1 target gene in feedback regulation of HSF1 and the HSR. To investigate these mechanisms, we will integrate sophisticated technologies in the field of transcription regulation with established biochemical, genetic and genomic methods. Our studies will provide the knowledge required for the development of therapeutic interventions that promote or inhibit specific programs directed by HSF1. Ultimately, this may enable us to modulate HSF1's non-canonical programs which are implicated in an ever-expanding array of disease states.

蛋白质稳态（蛋白抑制）或蛋白质组的适当折叠和功能对于细胞和 生物健康。对蛋白质的至关重要是一种进化上古老的细胞保护机制 在温度升高的细胞中的特征。这种机制称为热冲击响应 （HSR）现在众所周知可以预防许多多样化的蛋白质应激来源。 HSR的标志是 分子伴侣的深刻转录诱导称为热激蛋白（HSP），这是一个过程 由转录因子热休克因子1（HSF1）调节。因为这种快速稳固的转录 可以通过简单升高温度来引起诱导，HSR已被用作模型系统 基因表达场数十年。因此，控制HSF1激活和转录的过程 热休克时的调节已被广泛研究。但是，累积了最后的证据 十年揭示了HSF1功能的更复杂的图片。我们发现在癌症中，HSF1直接 调节参与细胞过程的基因的转录，这些基因远远超出了蛋白质折叠。 与经典的高铁不同的方式。在其他生理环境中的HSF1研究中，这是反映的 例如在肿瘤微环境和生物体发育中。启用HSF1的机制 调节性可塑性以及将不同HSF1调节基因集中的基本逻辑与 HSF1在蛋白抑制中的作用尚不清楚。在这里，我们建议将癌症用作模型系统 研究HSF1非规范调节作用的机制。通过一系列无偏的蛋白质组学 在这种不同的生理环境下，我们确定了HSF1至关重要的因素，这是一个令人惊讶的因素 非经典HSF1靶基因在HSF1和HSR的反馈调节中的多方面作用。调查 这些机制，我们将在转录调节领域的复杂技术与 建立的生化，遗传和基因组方法。我们的研究将为您提供所需的知识 开发促进或抑制HSF1指导的特定计划的治疗干预措施。最终， 这可能使我们能够调节HSF1的非规范程序，该程序与不断扩展的数组有关 疾病状态。