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

摘要：热休克转录因子1(HSF1)在细胞蛋白质中起核心作用 动态平衡(蛋白质平衡)，对机体健康有精确的调节。通过以下方式激活HSF1 胞浆和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)。HSF1也在特定的生理条件下被激活 调节发育、生殖、长寿、能量代谢。相反，反常的 HSF1的激活支持恶性肿瘤。而转录组和调控机制 已经对HSR中的HSF1进行了广泛的研究，对于 生理学中HSF1的程序性激活和疾病中HSF1的调节失调。具体来说， 人们很少了解：1为什么HSF1对某些细胞类型或细胞状态是必不可少的，以及 对别人来说是可有可无的，2&>是什么机制决定了HSF1的S调节和活动 这些生理和病理条件。我的实验室已经建立了动物和细胞模型 来解决这些问题。以线虫线虫为模型和遗传工具 我们新开发的，我们发现在祖细胞的种系中需要HSF1 以脱离HSR的方式进行扩散，这一必要条件由IGF-1/PI3K规定 发信号。我们将探索IGF-1/PI3K通路如何调节生殖细胞中的HSF1功能 通过细胞自主和非自主机制。与此同时，我们使用的是癌细胞系 了解HSF1的S在细胞异常增殖中的作用，其中HSF1的转录程序 已知HSF1不同于HSR。我们最近发现了上位性相互作用因素 HSF1通过CRISPR筛选在前列腺癌细胞中的增殖和存活。指导原则 结果，我们将研究HSF1在细胞周期进程中的作用及其通过 复制偶联核小体组装因子CHAF1B。通过这些研究，我们期望 揭示HSF1的依赖于环境的要求，并确定指定 HSF1在生殖系发育和未控制癌症中的独特转录程序 细胞增殖不同于典型的HSR。我们的研究将建立一个框架， HSF1在其他生理过程中的未来研究及其潜在的治疗意义 针对HSF1在癌症中的特定调控途径的策略。

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.