Genetic integration of pRB and Hippo tumor suppressor pathways

描述（申请人提供）：视网膜母细胞瘤（Retinoblastoma, pRB）通路是一个关键的肿瘤抑制通路。它在正常发育中起着关键作用，而它的功能失活发生在大多数癌症中。E2F因子家族是pRB的关键下游靶点之一，E2F活性的失调被认为可以驱动肿瘤细胞的增殖。相比之下，人们对新的河马肿瘤抑制途径知之甚少。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，从而强调了其在影响恶性状态中的重要作用。通过果蝇模型系统，我们发现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具有很强的协同作用。这两种途径的联合失活会导致不适当的增殖，令人惊讶的是，会导致广泛的去分化。重要的是，串扰的这两个方面是相互独立的，反映了pRB途径的不同功能。本提案中的实验将使用多种方法和新开发的工具来定义两种途径之间合作的细胞机制，并在体内测试这些机制的重要性。在Aim 1中，我们将破译Hippo和RB通路在限制细胞增殖方面的e2f依赖性合作。在Aim 2中，我们将研究这两种途径如何整合以维持分化状态。这些知识最终可能形成操纵通路的基础，并可能有助于设计新的抗癌疗法来治疗癌症。

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.