Tumor Suppression

项目5：S. Lowe肿瘤抑制Hannon，Gregory J 项目总结（见说明）： 该项目研究肿瘤抑制基因（TSG）网络及其破坏如何影响恶性行为。最初基于癌基因可以激活p53以促进细胞凋亡的观察，我们的早期努力涉及研究p53驱动细胞凋亡的机制以及在促进肿瘤发生期间如何抑制p53效应物或解除调节的存活信号传导。我们发现了几种新的癌基因调节因子诱导的细胞凋亡有助于肿瘤发生，并验证了作为治疗靶点的细胞存活的翻译控制。利用我们与Greg Hannon开发的可诱导RNAi技术，我们还发现肿瘤中内源性p53的再激活 依赖于环境，p53可能有效地触发细胞凋亡或衰老，从而确立了p53缺失在肿瘤维持中的作用。最后，利用该计划中开发的小鼠模型的独特功能，我们通过候选基因测试和体内筛选，鉴定并验证了几种新的癌基因和超过35种与人类癌症相关的新TSGs。展望未来，该项目将继续创新， 在生物学和技术水平上，采取更全面的方法研究肿瘤抑制剂，特别关注它们在胃肠道恶性肿瘤中的作用，并着眼于开发新的治疗靶点。具体来说，我们将在几种胃肠道恶性肿瘤中识别和表征新的TSG，研究非常常见但知之甚少的大染色体缺失对癌症发展的作用，探索关键TSG在肿瘤维持中的作用，并进行负选择RNAi筛选，以识别并表征TSG丢失造成的潜在漏洞。在实验上，我们将利用人类胃肠道癌症的基因组分析来为小鼠的功能研究提供信息，并实施一套新的RNAi工具和动物建模方法，以提高我们分析的成本效益和速度。这些研究的成功完成将确定与人类胃肠道恶性肿瘤相关的新基因，并确定它们如何影响疾病行为。我们的努力还可以确定新的治疗靶点，用于治疗TSG突变的癌症，否则很难在治疗上加以利用。为了实现这些目标，我们 该项目将产生一个蓝图，可以应用于其他基因和肿瘤类型。我们的目标是更全面地了解肿瘤抑制网络，并确定与特定癌症基因型相关的治疗靶点。

Project 5: S. Lowe Tumor Supression Hannon, Gregory J PROJECT SUMMARV (See instructions): This project studies tumor-suppressor gene (TSG) networks and how their disruption influences malignant behavior. Initially based on its observation that oncogenes can activate p53 to promote apoptosis, our early efforts involved studying mechanisms whereby p53 drives apoptosis and how suppression of p53 effectors or deregulated survival signaling can circumvent during promote tumorigenesis.Over the last funding cycle, we identified several new regulators of oncogene-induced apoptosis that contribute to tumorigenesis and validated translational control of cell survival as a therapeutic target. Taking advantage of inducible RNAi technology we developed with Greg Hannon, we also showed that reactivation of endogenous p53 in tumors potently triggered apoptosis or senescence depending on context, thus establishing a role for p53 loss in tumor maintenance. Finally, exploiting unique features of the mouse models developed in the program we, through candidate gene testing and in vivo screens, identified and validated several new oncogenes and over 35 new TSGs that are relevant to human cancer. Moving forward, the project will continue to innovate at both the biological and technical levels, taking a more comprehensive approach towards studying tumor suppressors, with a particular focus on their action in gastrointestinal malignancies and an eye towards developing new therapeutic targets. Specifically, we will identify and characterize new TSGs in several gastrointestinal malignancies, study the role of extremely common but poorly understood large chromosomal deletions on cancer development, explore the action of key TSGs in tumor maintenance, and perform negative selection RNAi screens to identify and then characterize potential vulnerabilities created by TSG loss. Experimentally, we will take advantage of genomic analyses of human gastrointestinal cancers to inform functional studies in mice, and implement a suite of new RNAi tools and animal modeling approaches to increase the cost effectiveness and pace of our analyses. Successful completion of these studies will identify new genes relevant to human gastrointestinal malignancies and determine how they influence disease behavior. Our efforts may also identify new therapeutic targets for treating cancers with TSG mutations, which have otherwise been difficult to exploit therapeutically. In addressing these aims, our project will produce a blueprint that can be applied to other genes and tumor types. Our goal is to gain a more comprehensive understanding of tumor suppressor networks and identify therapeutic targets relevant to specific cancer genotypes.