Roles of heat shock transcriptional factor 1 in cell proliferation independent of the heat shock response

热休克转录因子 1 在细胞增殖中的作用与热休克反应无关

• 批准号: 10251924
• 负责人: Jian Li
• 金额: $ 43.7万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2022-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251924
• 关键词: Abnormal Cell; Address; Animal Model; Animals; CRISPR screen; Caenorhabditis elegans; Cancer cell line; Cell Cycle Progression; Cell Nucleus; Cell Proliferation; Cell model; Cells; Coupled; Cytosol; Development; Disease; Energy Metabolism; Future; Gene Expression; Genetic; Genetic Transcription; Germ Cells; Health; Heat-Shock Response; Insulin-Like Growth Factor I; Knowledge; Light; Longevity; Malignant Neoplasms; Mission; Modeling; Nematoda; Nucleosomes; Pathologic; Pathway interactions; Physiological; Physiological Processes; Physiology; Play; Proteins; Regulation; Regulatory Pathway; Regulon; Reproduction; Research; Role; Signal Transduction; Specific qualifier value; Stress; System; Therapeutic; cancer cell; cell type; gene drive system; heat shock transcription factor; insight; programs; prostate cancer cell; proteostasis; proteotoxicity; response; stem cell proliferation; tool; transcriptome

Abstract: The heat shock transcriptional factor 1 (HSF1) plays central roles in cellular protein homeostasis (proteostasis), and is precisely regulated for organismal health. HSF1 is activated by proteotoxic stresses in the cytosol and nucleus, and induces the conserved protective response called the heat shock response (HSR). HSF1 is also activated in specific physiological conditions to regulate development, reproduction, longevity and energy metabolism. Conversely, aberrant activation of HSF1 supports malignancy. While the transcriptome and regulatory mechanisms for HSF1 in the HSR have been extensively studied, significant knowledge gaps exist for programmed activation of HSF1 in physiology and dysregulation of HSF1 in diseases. Specifically, it is poorly understood: 1> why HSF1 is essential for certain cell types or cellular states and dispensable for others, and 2> what mechanisms determine HSF1's regulons and activities in those physiological and pathological conditions. My lab has established animal and cell models to address these questions. Taking the nematode C. elegans as a model and the genetic tools we newly developed, we have found that HSF1 is required in the germline for progenitor cell proliferation in a manner uncoupled from the HSR, and this requisite is dictated by IGF-1/PI3K signaling. We will explore how the IGF-1/PI3K pathway regulates HSF1 functions in germ cells by cell-autonomous and non-autonomous mechanisms. Meanwhile, we are using cancer cell lines to understand HSF1's roles in abnormal cell proliferation, where the transcriptional program of HSF1 is known to be distinct from the HSR. We have recently identified epistatic interactors of HSF1 in proliferation and survival through CRISPR screens in prostate cancer cells. Guided by the results, we will study the roles of HSF1 in cell-cycle progression and its regulation by the replication-coupled nucleosome assembly factor CHAF1B. Through these studies, we expect to uncover the context-dependent requirements for HSF1, and identify the mechanisms that specify the unique transcriptional programs of HSF1 in germline development and uncontrolled cancer cell proliferation from those of the canonical HSR. Our research will establish a framework for future studies on HSF1 in other physiological processes, and shed light on potential therapeutic strategies that target the specific regulatory pathways of HSF1 in cancer.

摘要：热休克转录因子 1 (HSF1) 在细胞蛋白中发挥核心作用 体内平衡（蛋白质平衡），并受到精确调节以保证机体健康。 HSF1 被激活 细胞质和细胞核中的蛋白毒性应激，并诱导保守的保护反应，称为 热休克反应（HSR）。 HSF1在特定的生理条件下也会被激活来调节 发育、繁殖、寿命和能量代谢。相反，异常激活 HSF1 支持恶性肿瘤。 HSR中HSF1的转录组和调控机制 已被广泛研究，但对于 HSF1 的程序激活存在显着的知识差距 疾病中 HSF1 的生理学和失调。具体来说，了解甚少：1>为什么是HSF1 对于某些细胞类型或细胞状态是必需的，而对于其他细胞类型或细胞状态是可有可无的，并且 2> 什么 机制决定了HSF1在生理和病理过程中的调节子和活性 状况。我的实验室建立了动物和细胞模型来解决这些问题。采取 以线虫秀丽隐杆线虫为模型和我们新开发的遗传工具，我们发现 HSF1 在生殖系中是祖细胞增殖所必需的，其方式与 HSR 无关， 这一必要条件是由 IGF-1/PI3K 信号传导决定的。我们将探讨 IGF-1/PI3K 通路如何 通过细胞自主和非自主机制调节生殖细胞中的 HSF1 功能。 同时，我们正在使用癌细胞系来了解 HSF1 在异常细胞增殖中的作用， 其中 HSF1 的转录程序已知与 HSR 不同。我们最近有 通过 CRISPR 筛选，鉴定出 HSF1 在增殖和存活中的上位相互作用子 前列腺癌细胞。以结果为指导，我们将研究HSF1在细胞周期进展中的作用 及其受复制偶联核小体组装因子 CHAF1B 的调节。通过这些 研究中，我们期望揭示 HSF1 的上下文相关要求，并确定 指定 HSF1 在种系发育中的独特转录程序的机制 典型 HSR 中不受控制的癌细胞增殖。我们的研究将建立一个 为未来 HSF1 在其他生理过程中的研究提供框架，并揭示其潜力 针对癌症中 HSF1 特定调节途径的治疗策略。