Tumor Suppression

肿瘤抑制基因网络的作用是限制恶性肿瘤的生长，并能影响肿瘤的反应。 传统的和有针对性的抗癌药物。项目6（肿瘤抑制）感兴趣的是 揭示了参与将增殖与凋亡性细胞死亡偶联的先天性肿瘤抑制机制， 并确定使这些保护措施失效的突变如何影响肿瘤发生。我们以前使用 腺病毒E1A蛋白，以证明癌基因诱导的细胞凋亡如何被激活和执行 通过p53依赖和独立机制。最近，我们使用小鼠模型来建立 癌基因诱导的细胞凋亡在肿瘤抑制中的重要性，并确定了关键的细胞凋亡调节因子 其激活或破坏在肿瘤发生过程中与Myc协同作用。此外，我们的项目 开发了一些强有力的工具来探测体内肿瘤抑制基因网络，包括嵌合小鼠 淋巴瘤和肝细胞癌模型，以及体内RNAi技术抑制基因功能 以稳定或可逆的方式。展望未来，我们将继续探索 癌基因诱导的细胞凋亡在体内，现在采取比较的方法，检查Myc诱导的 淋巴癌和上皮癌中的肿瘤发生，并开发用于鉴定和 表征体内肿瘤抑制网络中的关键基因。首先，我们将描述p53依赖性 癌基因诱导的凋亡程序的独立组成部分，并确定它们如何影响 不同肿瘤类型的肿瘤发生。第二，我们将探讨如何解除管制的生存信号，通过 PIS激酶途径或通过改变的翻译控制逃避癌基因诱导的细胞凋亡并促进 肿瘤发生第三，我们将使用条件RNA干扰技术来确定p53的作用， p53突变在肿瘤维持中的作用最后，我们将进行高通量遗传筛选， 肿瘤抑制网络的组成部分，其破坏促进体内肿瘤发生。通过 了解癌基因如何参与凋亡网络以及肿瘤细胞如何逃避这一过程，我们 希望对先天肿瘤抑制机制的运作产生新的见解，并确定新的 药物靶点和治疗方法。

Tumor suppressor gene networks act to limit the growth of malignant tumors and can influence the response of tumors to conventional and targeted anticancer agents. Project 6 (Tumor Suppression) is interested in uncovering innate tumor suppressive mechanisms involved in coupling proliferation to apoptotic cell death, and determining how mutations that disable these safeguards influence tumorigenesis. We previously used the adenoviral E1A protein to demonstrate how oncogene-induced apoptosis can be activated and executed through p53-dependent and independent mechanisms. More recently, we used mouse models to establish the importance of oncogene-induced apoptosis in tumor suppression, and identified key apoptotic regulators whose activation or disruption cooperates with Myc during tumorigenesis. In addition, our project has developed some powerful tools to probe tumor suppressor gene networks in vivo, including chimeric mouse models of lymphoma and hepatocellular carcinoma, and in vivo RNAi technology to suppress gene function in a stable or reversible manner. Moving forward, we will continue to explore the underlying mechanisms of oncogene-induced apoptosis in vivo, now taking a comparative approach that examines Myc-induced tumorigenesis in a lymphoid and epithelial cancer, and exploiting rapid methods for identifying and characterizing crucial genes in tumor suppressor networks in vivo. First, we will characterize p53-dependent and independent components of oncogene-induced apoptotic programs and determine how they impact tumorigenesis in distinct tumor types. Second, we will explore how deregulated survival signaling through the PIS kinase pathway or via altered translational control evades oncogene-induced apoptosis and promotes tumorigenesis. Third, we will use conditional RNA interference technology to determine the role of p53 and p53 mutations in tumor maintenance. Finally, we will conduct high throughput genetic screens to identify components of tumor suppressor networks whose disruption promotes tumorigenesis in vivo. By understanding how oncogenes engage the apoptotic network and how tumor cells escape this process, we hope to produce new insights into the workings of innate tumor suppressor mechanisms and identify new drug targets and therapeutic approaches.