NOVEL CARCINOGEN INDUCED CELL CYCLE CHECKPOINT

该项目的长期目标是阐明 环境多环芳烃（PAH）诱导细胞的基础 周期检查点控制。 我们发现了一种新的细胞周期 检查点由芳香烃诱导的DNA损伤引起。 PAH- 激活的检查点将增殖细胞阻滞在细胞周期的G1期， 细胞周期 在S期之前停止生长可以防止潜在的错误- 易受损伤的DNA的诱变复制。 拟议的实验 在这里试图了解分子机制（S），其中PAH- 诱导的检查点施加在细胞上，最终， 机制在转换过程中被转义。 我们的初步研究 提出了肿瘤抑制剂的新的和重要的作用（视网膜母细胞瘤， 或Rb和p53）和G1信号转导通路在PAH诱导的 检查点控制 Rb和p53基因在肿瘤的发生发展中起重要作用。 防止恶性肿瘤，并在许多人中突变或缺失 癌的 因此，我们的初步数据提供了一个新的和直接的联系 环境中多环芳烃的细胞效应与人类 恶性肿瘤。这些研究将检验Rb、G1 促有丝分裂信号转导事件和p53在调节细胞增殖中的作用 对PAH的反应 本项目的具体目标是：（1）测试 假设PAH诱导的细胞周期检查点是Rb- 调解。 (2)为了检验PAH诱导的检查点 结果从有丝分裂G1信号转导事件的修改。 (3)为了检验p53在PAH修复中发挥作用的假设， 加合DNA 我们将使用功能丧失（病毒表达）， 癌基因）和功能获得（肿瘤的异位表达 敲除肿瘤抑制因子缺陷细胞中的抑制因子）策略 检测p53和Rb在细胞对多环芳烃反应中的作用。 此外，我们将分析促有丝分裂信号的PAH敏感性 G1期间的级联反应，以确定推定的PAH诱导的 病变。 这些研究将确定新的分子机制， 检查点控制 这些信息可以使合理的设计， 新的化学疗法来操纵检查点通路。 这些药物可以 有助于预防和治疗PAH诱导的（以及可能的其他）恶性肿瘤。

The broad long-term goal of this project is to elucidate the molecular basis of environmental Polycyclic Aryl-Hydrocarbon (PAH)-induced cell cycle checkpoint control. We have identified a novel cell cycle checkpoint resulting from aryl-hydrocarbon-induced DNA damage. The PAH- activated checkpoint arrests proliferating cells in the G1 phase of the cell cycle. Growth arrest prior to S-phase prevents potentially error- prone and mutagenic replication of damaged DNA. Experiments proposed here seek to understand the molecular mechanism(s) whereby the PAH- induced checkpoint is imposed upon cells and, ultimately, how this mechanism is escaped during transformation. Our preliminary studies suggested new and important roles for tumor suppressors (Retinoblastoma, or Rb, and p53) and G1 signal transduction pathways in PAH-induced checkpoint control. The Rb and p53 genes play important roles in guarding against malignancy and are mutated or absent in many human cancers. Therefore, our preliminary data provided a new and direct link between the cellular effects of environmental PAHs and human malignancies. These studies will test the putative roles of Rb, G1 mitogenic signal transduction events, and p53 in regulating cellular responses to PAHs. The specific aims of this project are: (1) To test the hypothesis that the PAH-induced cell cycle checkpoint is Rb- mediated. (2) To test the hypothesis that the PAH-induced checkpoint results from modification of mitogenic G1 signal transduction events. (3) To test the hypothesis that p53 plays a role in repair of PAH- adducted DNA. We will use loss-of-function (expression of viral oncogenes) and gain-of-function (ectopic expression of tumor suppressors in knockout tumor suppressor-deficient cells) strategies to test the roles of p53 and Rb in cellular responses to PAHs. Additionally, we will analyze the PAH-sensitivity of mitogenic signaling cascades during G1 in order to identify the putative PAH-induced lesion(s). These studies will identify novel molecular mechanisms of checkpoint control. This information may enable the rational design of new chemotherapies to manipulate checkpoint pathways. Such drugs could help prevent and treat PAH-induced (and possibly other) malignancies.