Regulation and interplay of Heat Shock Factors in growth-associated proteotoxic stresses

蛋白质稳态（蛋白质稳态），或蛋白质组的正确折叠和功能，对于细胞和 有机体健康蛋白质稳态的关键是一种进化上古老的细胞保护机制， 其特征在于细胞经受高温。这种机制，称为热休克反应 (HSR)现在已知，它能保护机体免受多种蛋白毒性应激源的侵害。高铁的一个特点是 分子伴侣被称为热休克蛋白（HSPs）的深刻转录诱导， 由转录因子热休克因子1（HSF 1）调节。因为这种快速而强大的转录 诱导可以引起简单地增加温度，HSR已被用作模型系统中， 基因表达领域几十年来因此，控制HSF 1激活和转录的过程 对热休克的调节已被广泛研究。然而，过去一年来积累的证据表明， 十年来，HSF 1的功能揭示了一个更复杂的画面。我们发现在癌症中，HSF 1直接 调节参与细胞过程的基因的转录，这些过程远远超出蛋白质折叠， 与传统的HSR不同。这已经反映在HSF 1在其他生理环境中的研究中， 例如在肿瘤微环境和生物体发育中。使HSF1能够 调节可塑性，以及连接不同的HSF1调节基因组的潜在逻辑， HSF1在蛋白质稳定中的作用还不清楚。在这里，我们建议使用癌症作为模型系统， 研究HSF1的非经典调节作用的机制。通过一系列无偏见的蛋白质组学 和遗传筛选，我们确定了在这种独特的生理背景下对HSF 1至关重要的因子， 非典型HSF1靶基因在HSF1和HSR反馈调节中的多方面作用。探讨 这些机制，我们将整合转录调控领域的尖端技术， 建立了生物化学、遗传学和基因组学方法。我们的研究将提供所需的知识， 开发促进或抑制由HSF 1指导的特定程序的治疗干预。最后， 这可能使我们能够调节HSF 1的非规范程序，这些程序涉及不断扩展的阵列 疾病状态。

Protein homeostasis (proteostasis), or the proper folding and function of the proteome, is vital for cellular and organismal health. Critical to proteostasis is an evolutionarily ancient cytoprotective mechanism originally characterized in cells subjected to elevated temperatures. This mechanism, termed the Heat Shock Response (HSR), is now known to protect against many diverse sources of proteotoxic stress. A hallmark of the HSR is the profound transcriptional induction of molecular chaperones known as heat shock proteins (HSPs), a process regulated by the transcription factor Heat Shock Factor 1 (HSF1). Because this rapid and robust transcriptional induction can be provoked by simply increasing temperature, the HSR has been used as a model system in the gene expression field for decades. As such, the processes that govern HSF1 activation and transcriptional regulation upon heat shock have been extensively studied. However, evidence accumulating over the last decade has revealed a more complicated picture of HSF1 function. We have found that in cancer, HSF1 directly regulates the transcription of genes involved in cellular processes which extend far beyond protein folding, in a manner distinct from the classic HSR. This has been mirrored in studies of HSF1 in other physiological contexts, such as in the tumor microenvironment and in organismal development. The mechanisms which enable HSF1's regulatory plasticity, and the underlying logic that connects the disparate set of HSF1-regulated genes with HSF1's role in proteostasis, is not well understood. Here we propose to use cancer as a as a model system to study the mechanisms that underlie HSF1's non-canonical regulatory roles. Through a series of unbiased proteomic and genetic screens we identify a factor critical for HSF1 in this distinct physiological context, and a surprising multifaceted role for a non-canonical HSF1 target gene in feedback regulation of HSF1 and the HSR. To investigate these mechanisms, we will integrate sophisticated technologies in the field of transcription regulation with established biochemical, genetic and genomic methods. Our studies will provide the knowledge required for the development of therapeutic interventions that promote or inhibit specific programs directed by HSF1. Ultimately, this may enable us to modulate HSF1's non-canonical programs which are implicated in an ever-expanding array of disease states.