Genetic integration of pRB and Hippo tumor suppressor pathways

描述（由申请人提供）：视网膜母细胞瘤（pRB）通路是一种关键的肿瘤抑制通路。它在正常发育中起着关键作用，而其功能失活发生在大多数癌症中。E2F因子家族是pRB的关键下游靶标之一，并且认为失调的E2F活性驱动肿瘤细胞中的增殖。相比之下，对新型Hippo肿瘤抑制通路的了解较少。然而，最近在果蝇和哺乳动物中的研究表明，Hippo通路控制组织稳态，而其失调导致肿瘤发生，因此，强调了其在影响恶性状态中的重要作用。利用果蝇模型系统，我们已经发现Hippo通路与pRB通路在限制细胞增殖和维持终末分化状态方面强烈合作。两种途径的联合失活引起不适当的增殖，令人惊讶的是，引起广泛的去分化。重要的是，串扰的这两个方面是彼此独立的，并且反映了pRB通路的不同功能。本提案中的实验将使用方法和新开发的工具的组合来定义两种途径之间合作的细胞机制，并测试这些机制在体内的重要性。在目标1中，我们将破译E2F依赖的方面的合作，河马和RB途径限制细胞增殖。在目标2中，我们将研究这两种途径如何整合以维持分化状态。这些知识最终可能成为操纵这些途径的基础，并可能有助于设计治疗癌症的新抗癌疗法。 公共卫生相关性：拟议的研究的重点是研究潜在的合作机制之间的pRB途径和一种新的Hippo肿瘤抑制剂途径在控制细胞增殖和维持分化状态在体内。值得注意的是，我们已经发现，两种途径的联合失活导致显着的去分化。因此，拟议的研究结果可能有助于设计有效的抗癌疗法，特别是那些基于分化诱导剂的疗法。

DESCRIPTION (provided by applicant): The Retinoblastoma (pRB) pathway is a key tumor-suppressor pathway. It plays a pivotal role in normal development while its functional inactivation occurs in most cancers. The family of E2F factors is one of the key downstream targets of pRB and deregulated E2F activity is thought to drive proliferation in tumor cells. In contrast, less is known about novel Hippo tumor-suppressor pathway. However, recent studies in flies and in mammals suggested that Hippo pathway controls tissue homeostasis while its deregulation leads to tumorigenesis, thus, underscoring its important role in influencing the malignant state. Using a Drosophila model system, we have discovered that Hippo pathway strongly cooperates with pRB pathway in limiting cell proliferation and in maintenance of the state of terminal differentiation. Combined inactivation of both pathways gives rise to inappropriate proliferation and, surprisingly, to extensive dedifferentiation. Importantly, these two facets of a crosstalk are independent of each other and reflect distinct functions of the pRB pathway. Experiments in this proposal will use a combination of approaches and newly developed tools to define the cellular mechanisms underlying cooperation between the two pathways and to test the importance of these mechanisms in vivo. In Aim 1, we will decipher an E2F-dependent aspect of cooperation between Hippo and RB pathways in limiting cell proliferation. In Aim 2 we will investigate how the two pathways are integrated to maintain the differentiated state. This knowledge could eventually form a basis for manipulating the pathways and may help in designing new anticancer therapies for treating cancers. PUBLIC HEALTH RELEVANCE: The focus of proposed research is to investigate the mechanisms underlying cooperation between the pRB pathway and a novel Hippo tumor suppressor pathway in control of cell proliferation and maintenance of the differentiated state in vivo. Notably, we have discovered that combined inactivation of both pathways leads to dramatic dedifferentiation. Therefore the results of the proposed research may help in designing of efficient anticancer therapies particularly those based on differentiation-induced agents.