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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

基本信息

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
项目类别：
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

项目摘要

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（proteostasis），或蛋白质组的适当折叠和功能，对细胞和细胞的生长至关重要