Gene Repression by HSF1 during hyperthermia and stresses

描述（由申请人提供）：热休克导致戏剧性的。转变 从参与生长和分化功能的基因表达到 胁迫基因表达。我们最近发现热休克因子1 （HSF 1），热休克反应的分子协调者，是一种有效的 （非热休克）基因转录的阻遏物。我们的目标是确定 HSF 1在免疫反应中的基因抑制， 增殖和细胞对应激的反应。通过研究 基因抑制HSF 1和潜在的分子机制，我们的目标是 确定HSF 1在免疫应答中的基因抑制作用， 细胞应激反应有三个具体目标，其中包括： 首先，我们将研究潜在的抑制的分子机制， IL-1和c-fos的表达。我们将研究转录阶段 HSF 1的作用和关键蛋白质或DNA伴侣， 调解镇压。这将有助于全面的遗传图谱的 HSF 1内介导阻遏的结构域及其与 靶细胞的转录机制。在第二个目标中，我们将研究 HSF 1对基因阻遏的细胞内调节。我们将调查一个 HSF 1中高度保守的磷酸化位点的数量， 抑制，并将检查磷酸化的功能作用， 通过HSF 1控制基因表达/阻遏。最后，我们将调查 基因阻遏在许多系统中的生理作用，包括 免疫反应和细胞应激反应。这涉及到识别 在单核细胞活化和促有丝分裂刺激期间诱导的基因， 被HSF 1抑制。我们将使用高密度基因微阵列表达 分析以确定HSF 1过程中基因表达/抑制的总体变化 activation.进一步的实验将解决基因抑制的地方， HSF 1参与应激反应，可能在体温过高中发挥重要作用。主导 在本研究中已经鉴定了HSF 1抑制的负抑制剂， 它们将用于转染细胞中，以研究 HSF 1的基因阻遏。

DESCRIPTION (provided by applicant): Heat shock results in a dramatic. shift in gene expression from genes involved in growth and differentiated function to stress gene expression. We have recently discovered that heat shock factor 1 (HSF1), the molecular coordinator of the heat shock response is a potent repressor of (non-heat shock) gene transcription. We aim to determine the role of gene repression by HSF1 in the immune response, the regulation of proliferation and in cellular responses to stress. By studying the profile of genes repressed by HSF1 and the underlying molecular mechanisms, we aim to determine the gene repression role of HSF1 in the immune response and the cellular stress response. There are three specific aims, which include: Firstly, we will examine the molecular mechanisms underlying repression of interleukin 1 and c-fos by HSF1. We will study the stage of transcriptional activation at which HSF1 acts and the critical protein or DNA partners that mediate repression. This will be aided by comprehensive genetic mapping of the domains within HSF1 that mediate repression and their interactions with the transcriptional machinery of target cells. In the second aim, we will study the intracellular regulation of gene repression by HSF1. We will investigate a number of highly-conserved phosphorylation sites within HSF1 that regulate repression and will examine the functional role of phosphorylation in the control of gene expression/repression by HSF1. Finally, we will investigate the physiological role of gene repression in a number of systems, including the immune response and the cellular stress response. This involves identifying genes induced during monocyte activation and mitogenic stimulation that are repressed by HSF1. We will use high density gene microarray expression profiling to identify global changes in gene expression/repression during HSF1 activation. Further experiments will address the place of gene repression by HSF1 in the stress response and is potential role in hyperthermia. Dominant negative inhibitors of HSF1 repression have been identified in this study and they will be used in transfected cells to study the cellular consequences of gene repression by HSF 1.