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（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， 蛋白质毒性应激在胞质溶胶和细胞核，并诱导保守的保护性反应 这就是所谓的热休克反应（HSR）。HSF 1也在特定的生理条件下被激活 调节发育、生殖、寿命和能量代谢。相反，异常 HSF 1的激活支持恶性肿瘤。虽然转录组和调控机制， HSR中的HSF 1已被广泛研究，对于HSR中的HSF 1存在显著的知识空白。 HSF 1在生理上的程序性激活和疾病中的HSF 1失调。具体地说， 目前还不清楚：1>为什么HSF 1对某些细胞类型或细胞状态是必需的， 2>什么机制决定HSF 1的调节子和活动， 这些生理和病理条件。我的实验室建立了动物和细胞模型 来解决这些问题。以线虫C.作为一个模型和遗传工具， 我们新开发的，我们发现HSF 1是需要在生殖系祖细胞 以与HSR解偶联的方式增殖，这一必要条件由IGF-1/PI 3 K决定 发信号。我们将探讨IGF-1/PI 3 K通路如何调节生殖细胞中的HSF 1功能 通过细胞自主和非自主机制。与此同时，我们使用癌细胞系 为了了解HSF 1在异常细胞增殖中的作用， 已知HSF 1与HSR不同。我们最近已经确定了上位相互作用， HSF 1在前列腺癌细胞中通过CRISPR筛选的增殖和存活。指导 因此，我们将研究HSF 1在细胞周期进程中的作用以及HSF 1在细胞周期中的调节作用。 复制偶联核小体组装因子CHAF 1B。通过这些研究，我们希望 揭示HSF 1的上下文相关需求，并确定指定 HSF 1在生殖系发育和不受控制的癌症中的独特转录程序 细胞增殖从那些典型的HSR。我们的研究将建立一个框架， HSF 1在其他生理过程中的未来研究，并阐明潜在的治疗方法 针对癌症中HSF 1的特异性调节途径的策略。

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.