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 蛋白毒性应激在细胞质和细胞核中，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以调节 发育、繁殖、长寿和能量代谢。相反，异常激活 HSF1支持恶性肿瘤。而HSF1在HSR中的转录组和调控机制 已经进行了广泛的研究，但在HSF1的程序性激活方面存在显著的知识差距 HSF1在疾病中的生理学和调节失调。具体地说，人们对此知之甚少：1；为什么要进行HSF1 对于某些细胞类型或细胞状态是必不可少的，而对其他细胞类型或细胞状态则是可有可无的，以及2&>；什么 机制决定了HSF1在生理和病理中的S调节和活性 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。参加了 线虫作为模型和我们新开发的遗传工具，我们发现 在胚系中需要HSF1以与HSR分离的方式进行祖细胞增殖， 这一必要条件是由IGF-1/PI3K信令规定的。我们将探索IGF-1/PI3K通路是如何 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，我们正在利用癌细胞株来了解HSF1的S在细胞异常增殖中的作用， 已知HSF1的转录程序与HSR不同。我们最近做了 通过CRISPR筛选确定HSF1在增殖和存活中的上位相互作用 前列腺癌细胞。在这些结果的指导下，我们将研究HSF1在细胞周期进程中的作用 并受复制偶联核小体组装因子CHAF1B的调控。通过这些 研究，我们希望揭示HSF1的上下文相关要求，并确定 在生殖系发育和发育过程中指定HSF1独特转录程序的机制 不受控制的癌细胞增殖不同于那些典型的HSR。我们的研究将建立一个 HSF1在其他生理过程中的未来研究框架，并揭示其潜力 针对HSF1在癌症中的特定调控途径的治疗策略。

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.