Genetic integration of pRB and Hippo tumor suppressor pathways

pRB 和 Hippo 肿瘤抑制途径的基因整合

基本信息

批准号：
8708116
负责人：
Maxim Frolov
金额：
$ 29.65万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708116
关键词：
Apoptosis Biochemical Biological Models Cancer Biology Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Maintenance Cell Proliferation Cell physiology Cells Cues Defect Development Drosophila genus E2F transcription factors Event Family Family member Financial compensation Future Gene Family Genetic Goals Growth Homeostasis Homologous Gene Human Knock-out Knowledge Lead Maintenance Malignant Neoplasms Mammals Masks Modeling Molecular Mus Pathway interactions Play Property Regulation Research Research Design Retinoblastoma Role S Phase Signal Transduction Testing Tissues Tumor Suppressor Proteins Work base cancer cell cancer therapy design fly genetic analysis genetic manipulation in vivo insight malignant state mutant neoplastic cell novel progenitor research study retinoblastoma tumor suppressor tool trait tumorigenesis

项目摘要

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.

描述（由申请人提供）：视网膜母细胞瘤（PRB）途径是关键的肿瘤抑制途径。它在正常发育中起关键作用，而其功能失活发生在大多数癌症中。 E2F因子的家族是PRB的关键下游靶标之一，而E2F的失调活性被认为可以促进肿瘤细胞中的增殖。相比之下，对新型河马肿瘤抑制途径知之甚少。然而，最近对苍蝇和哺乳动物的研究表明，河马途径控制组织稳态，而其放松管制会导致肿瘤发生，因此，强调了其在影响恶性状态的重要作用。使用果蝇模型系统，我们发现河马途径与PRB途径在限制细胞增殖和维持末端分化状态方面有着强烈的合作。两种途径的混合失活都会导致不适当的增殖，而且令人惊讶地导致大量推断。重要的是，串扰的这两个方面彼此独立，反映了PRB途径的不同功能。该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基础机制，并在体内测试这些机制的重要性。在AIM 1中，我们将在限制细胞增殖中破译河马和RB途径之间的E2F依赖性方面。在AIM 2中，我们将研究如何整合这两种途径以维持差异化状态。这些知识最终可能构成操纵途径的基础，并可能有助于设计用于治疗癌症的新抗癌疗法。