ROLE OF HSF2 IN THE STRESS RESPONSE TO HYPERTHERMIA

癌细胞对细胞毒性治疗的敏感性受到应激反应（如热休克反应）的抑制。我们的目标是研究我们实验室新发现的结果，该发现表明转录因子热休克因子2 （HSF2）被应激激活，并在介导细胞对高温和其他治疗的抗性中发挥作用。我们的目标是描述HSF2在细胞对癌症治疗和肿瘤微环境的应激反应中的作用。我们的假设是HSF2与包括HSF1在内的其他应激反应因子协同作用，调节HSP基因转录，诱导协调应激反应，导致分子伴侣的表达。我们将首先确定HSF2被招募到应激诱导启动子、结合DNA、与其他因子相互作用和激活转录的分子机制。我们的目标是确定HSF2中调控目标启动子活性的功能域，并确定HSF家族成员之间相互作用的机制。我们的假设是HSF家族成员之间复杂的形成调节应激反应启动子的反式激活。然后，我们将分析HSF2在人类恶性细胞应激反应中的作用。利用项目第一阶段制备的显性阴性和本构激活构建体，我们拟确定HSF1和HSF2在抗凋亡和克隆性细胞死亡中的相对作用，并揭示恶性细胞中HSF激活的机制。

The sensitivity of cancer cells to cytotoxic therapy is resisted by the expression of stress responses such as the heat shock response. We aim to investigate the consequences of novel finding made in our laboratory indicating that the transcription factor heat shock factor 2 (HSF2) is activated by stress and play a role in mediating the resistance of cells to hyperthermia and other treatments. We aim to delineate the role of HSF2 in the response of cells to the stresses of cancer therapy and the tumor microenvironment. Our hypothesis is that HSF2 acts cooperatively with other stress responsive factors including HSF1 to regulate HSP gene transcription and to induce a coordinate stress response that results in the expression of molecular chaperones. We will first determine the molecular mechanisms by which HSF2 is recruited to stress-inducible promoters, binds DNA, interacts with other factors and activates transcription. We aim to identify the functional domains in HSF2 that regulate the activity of target promoters and to determine the mechanisms of interaction between HSF family members. Our hypothesis is that complex formation between HSF family members regulates the trans- activation of stress-responsive promoters. We will then analyze the role of HSF2 within the stress response in human malignant cells. Using dominant negative and constitutively activated constructs prepared during the first phase of the project, we propose to determine the relative roles of HSF1 and HSF2 in resistance to apoptosis and clonogenic cell death and to uncover mechanisms of HSF activation in malignant cells.