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 调节发育、繁殖、寿命和能量代谢。反之，则异常 HSF1 的激活支持恶性肿瘤。虽然转录组和调控机制 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。具体来说， 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 那些生理和病理条件。我的实验室建立了动物和细胞模型 来解答这些问题。以线虫秀丽隐杆线虫为模型和遗传工具 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 发信号。我们将探讨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 众所周知，HSF1 与 HSR 不同。我们最近发现了上位相互作用子 通过 CRISPR 筛选前列腺癌细胞中 HSF1 的增殖和存活情况。指导者 根据结果，我们将研究 HSF1 在细胞周期进程中的作用及其调控 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 细胞增殖不同于典型 HSR 的细胞增殖。我们的研究将建立一个框架 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.