A Novel Carcinogen-Induced Cell Cycle Checkpoint

描述：（由申请人提供）该项目的广泛的长期目标 是阐明细胞周期检查点反应的分子基础， 多环芳烃（PAH）诱导的DNA损伤。细胞周期检查点 是重要的肿瘤抑制机制， 人类癌症肿瘤抑制检查点的丢失可能在以下方面发挥因果作用： 恶性肿瘤的发生和发展。 此外，细胞周期 可以在治疗上利用检查点来治疗人类肿瘤。因此，我们认为， 对检查站管理的了解将加深我们对 肿瘤发生的机制，并将影响我们治疗人类癌症的能力。 这项工作的具体目标有三个方面：（1）检验假设， ATM和/或ATR介导的信号传导途径抑制Chkl磷酸化， 芳香烃引起的S期阻滞。(2)为了检验这一假设 Chk 1底物蛋白是PAH诱导的S期细胞的下游效应物， 逮捕了(3)为了检验Radl 7和Radl/Rad 9/Husl蛋白质在细胞内表达的假设， 复合物介导的DNA损伤信号和细胞周期反应 芳基烃。这些研究将测试Chkl的激活机制， DNA损伤信号（SA 1）。 我们还将鉴定Chkl的效应子。 信号传导，负责PAH诱导的S期阻滞（SA 2）。 此外，我们将测试假定的DNA损伤传感器Rad 17的作用， Rad 1、Rad 9和Hus 1在调节Chk 1活性和S期阻滞中的作用（SA 3）。 我们将使用“功能丧失”策略来扰乱假定的DNA损伤 在培养的细胞系中的信号通路。这些策略包括表达 以及来自转基因的细胞系的用途 动物我们将测试由此产生的扰动对信号的影响。 多环芳烃的转导途径和细胞周期反应。这些实验将 确定新的肿瘤抑制检查点控制机制， 对抗环境致癌物。我们发现的信号通路 研究代表了合理设计的潜在新目标， 化疗来控制检查点。这些药物可以被利用 来预防和治疗人类癌症。

DESCRIPTION: (PROVIDED BY APPLICANT) The broad long-term goal of this project is to elucidate the molecular basis of cell cycle checkpoint responses to Polycyclic Aryl-Hydrocarbon (PAH)-induced DNA damage. Cell cycle checkpoints are important tumor suppressive mechanisms that are frequently abrogated in human cancers. Loss of tumor-suppressive checkpoints can play a causal role in the initiation and progression of malignancies. Additionally, cell cycle checkpoints can be exploited therapeutically to treat human tumors. Therefore, a knowledge of checkpoint regulation will further our understanding of mechanisms of tumorigenesis and will impact our ability to treat human cancers. The specific aims of this work are threefold: (1) To test the hypothesis that an ATM and/or ATR-mediated signaling pathway elicits Chkl phosphorylation and S-phase arrest in response to aryl-hydrocarbons. (2) To test the hypothesis that Chkl substrate proteins are downstream effectors of PAH-induced S-phase arrest. (3) To test the hypothesis that Radl7 and the Radl/Rad9/Husl protein complex mediate DNA damage signaling and cell cycle responses to aryl-hydrocarbons. These studies will test the mechanisms of activation of Chkl by DNA damage signals (SA 1 ). We will also identify the effectors of Chkl signaling that are responsible for PAH-induced S-phase arrest (SA 2). Furthermore, we will test the roles of the putative DNA damage-sensors Rad17, Rad1, Rad9, and Hus1 in regulation of Chkl activity and S-phase arrest (SA 3). We will use 'loss of function' strategies to perturb putative DNA damage signaling pathways in cultured cell lines. These strategies include expression of mutant dominant-negative proteins and the use of cell lines from transgenic animals. We will test the effects of the resulting perturbations on signal transduction pathways and cell cycle responses to PAHs. These experiments will identify novel tumor-suppressive checkpoint control mechanisms that protect against environmental carcinogens. The signaling pathways identified by our studies represent potential new targets for the rational design of chemotherapies to manipulate checkpoint control. Such drugs could be exploited to prevent and treat human cancers.