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

基本信息

批准号：
10796280
负责人：
Jian Li
金额：
$ 4.49万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
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/10796280
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

项目摘要

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（蛋白质稳态）并受到 HSF1 的精确调节以促进生物健康。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) 的 HSF1 在特定的生理条件下也会被激活。调节发育、繁殖、寿命和能量代谢。 HSF1 的激活支持恶性肿瘤，而转录组和调控机制。 HSR 中的 HSF1 已得到广泛研究，但存在重大知识差距生理学中 HSF1 的程序性激活和疾病中 HSF1 的失调。人们知之甚少： 1> 为什么 HSF1 对于某些细胞类型或细胞状态至关重要，以及 2> 哪些机制决定了 HSF1 的调节子和活性我的实验室已经建立了这些生理和病理条件。以线虫秀丽隐杆线虫为模型和遗传工具来解决这些问题。我们新开发的，我们发现HSF1是祖细胞生殖细胞中所必需的以与 HSR 分离的方式进行增殖，而这一必要条件是由 IGF-1/PI3K 决定的我们将探讨 IGF-1/PI3K 通路如何调节生殖细胞中的 HSF1 功能。同时，我们正在使用癌细胞系。了解 HSF1 在异常细胞增殖中的作用，其中转录程序已知 HSF1 与 HSR 不同，我们最近发现了的上位相互作用子。通过 CRISPR 筛选前列腺癌细胞中 HSF1 的增殖和存活。根据结果，我们将研究 HSF1 在细胞周期进程中的作用及其通过通过这些研究，我们期望复制偶联核小体组装因子 CHAF1B。揭示 HSF1 的上下文相关要求并确定指定的机制 HSF1 在种系发育和不受控制的癌症中的独特转录程序我们的研究将为细胞增殖建立一个框架。未来关于 HSF1 在其他生理过程中的研究并揭示潜在的治疗方法针对癌症中 HSF1 特定调节途径的策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of germline proteostasis by HSF1 and insulin/IGF-1 signaling.

DOI：
10.1042/bst20220616
发表时间：
2023-04-26
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
通讯作者：

Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance.

DOI：
10.3389/fragi.2022.899744
发表时间：
2022
期刊：
FRONTIERS IN AGING
影响因子：
0
作者：
Morphis, Allison C.;Edwards, Stacey L.;Erdenebat, Purevsuren;Kumar, Lalit;Li, Jian
通讯作者：
Li, Jian

Editorial: C. elegans MAPS the way: the 2022 C. elegans meeting on metabolism, aging, pathogenesis, and stress (MAPS 2022).

DOI：
10.3389/fphys.2023.1331912
发表时间：
2023
期刊：
Frontiers in physiology
影响因子：
4
作者：
通讯作者：

Insulin/IGF-1 signaling and heat stress differentially regulate HSF1 activities in germline development.

DOI：
10.1016/j.celrep.2021.109623
发表时间：
2021-08-31
期刊：
Cell reports
影响因子：
8.8
作者：
Edwards SL;Erdenebat P;Morphis AC;Kumar L;Wang L;Chamera T;Georgescu C;Wren JD;Li J
通讯作者：
Li J