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: 10701882
• 负责人: Jian Li
• 金额: $ 41万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701882
• 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; Longevity; Malignant Neoplasms; Mission; Modeling; Nematoda; Nucleosomes; PIK3CG gene; Pathologic; Pathway interactions; Physiological; Physiological Processes; Physiology; Play; Proliferating; Proteins; Regulation; Regulatory Pathway; Regulon; Reproduction; Research; Role; Signal Transduction; Specific qualifier value; Stress; System; Therapeutic; cancer cell; cell type; coping; 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（HSF 1）在细胞蛋白中起着重要作用 体内平衡（蛋白质平衡），并精确调节有机体的健康。HSF 1被激活， 细胞质和细胞核中的蛋白毒性应激，并诱导保守的保护性反应，称为 热休克反应（HSR）。HSF 1也在特定的生理条件下被激活，以调节 发育、生殖、寿命和能量代谢。相反， HSF 1支持恶性肿瘤。虽然HSR中HSF 1的转录组和调控机制 已被广泛研究，显着的知识差距存在的程序激活HSF 1在 HSF 1在疾病中的生理学和失调。具体来说，它是知之甚少：1>为什么HSF 1 对于某些细胞类型或细胞状态是必不可少的，而对于其他细胞类型或细胞状态是必需的，以及2>什么 HSF 1的调节子和活动在那些生理和病理的 条件我的实验室已经建立了动物和细胞模型来解决这些问题。以 线虫C.作为一个模型和我们新开发的遗传工具，我们发现， HSF 1在种系中以与HSR解偶联的方式为祖细胞增殖所需， 并且这种必要性由IGF-1/PI 3 K信号传导决定。我们将探讨IGF-1/PI 3 K通路如何 通过细胞自主和非自主机制调节HSF 1在生殖细胞中的功能。 同时，我们正在使用癌细胞系来了解HSF 1在异常细胞增殖中的作用， 其中已知HSF 1的转录程序不同于HSR。我们最近 通过CRISPR筛选确定了HSF 1在增殖和存活中的上位相互作用， 前列腺癌细胞根据这些结果，我们将研究HSF 1在细胞周期进程中的作用 以及通过复制偶联核小体组装因子CHAF 1B对其的调节。通过这些 研究，我们希望揭示HSF 1的上下文相关要求，并确定 在种系发育中指定HSF 1独特转录程序的机制， 不受控制的癌细胞增殖从那些典型的HSR。我们的研究将建立一个 HSF 1在其他生理过程中的未来研究框架，并揭示了潜在的 针对癌症中HSF 1的特异性调节途径的治疗策略。