Rb-Id2 Pathway in Mouse Development and Tumorigenesis

Rb-Id2 通路在小鼠发育和肿瘤发生中的作用

• 批准号: 7065201
• 负责人: ANNA LASORELLA
• 金额: $ 35.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7065201
• 关键词: SDS polyacrylamide gel electrophoresis; angiogenesis; apoptosis; autoradiography; cell differentiation; cell proliferation; cyclins; dendritic cells; erythropoiesis; gel mobility shift assay; growth /development; immunocytochemistry; immunoprecipitation; laboratory mouse; macrophage; neoplastic process; polymerase chain reaction; protein structure; retinoblastoma protein; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): In mammalian cells, the Retinoblastoma (Rb) tumor suppressor protein is essential to execute terminal cell cycle withdrawal, complete differentiation and secure cell survival. In the absence of Rb, mouse development is impaired and Rb-mutant embryos die at mid-gestation with severe defects in erythropoiesis and neurogenesis. The helix-loop helix protein Inhibitor of differentiation 2 (Id2) coordinates proliferation and differentiation. Id2 binds Rb and antagonizes its antiproliferative function. We have recently reported that ablation of the mouse Id2 gene rescues the phenotypic abnormalities and lethality of Rb-mutant embryos. These results have identified Id2 as a relevant target of tumor suppressor proteins, whose function must be restrained by Rb during development. The long-term goal of this work is to understand the role of Rb-Id2 complexes in proliferation, differentiation and tumorigenesis using genetically modified mouse models. We have found that Rb is essential for differentiation of the macrophage/dendritic cell lineage, a cell type required to support erythropoiesis in the fetal liver. This is an exciting novel finding that will allow us to dissect the most relevant Rb-null defect, in order to trace the molecular events directed by the Rb-Id2 pathway in erythropoiesis. We will also determine the target specificity of Id2 in cell proliferation and differentiation by discriminating Id2 and E2F functions in the absence of Rb. Finally, to establish the role of Id2 in tumorigenesis initiated by inactivation of Rb, we will use a mouse model in which mutation of Rb predisposes to pituitary cancer. These experiments will increase our understanding of the mechanisms by which Rb promotes cell cycle arrest and differentiation in normal cells and the perturbation of these mechanisms in cellular transformation.

描述（由申请人提供）：在哺乳动物细胞中，视网膜母细胞瘤（RB）抑制蛋白对于执行末端细胞周期戒断，完全分化和固定细胞存活至关重要。在不存在RB的情况下，小鼠发育受到损害，RB突变胚胎在妊娠中期死亡，促红细胞生成和神经发生严重缺陷。分化2（ID2）的螺旋环螺旋蛋白抑制剂坐在增殖和分化。 ID2结合RB并拮抗其抗增生功能。我们最近报告说，小鼠ID2基因的消融挽救了RB突变胚胎的表型异常和致死性。这些结果已将ID2确定为肿瘤抑制蛋白的相关靶标，其功能必须在发育过程中受RB的限制。这项工作的长期目标是了解RB-ID2复合物使用遗传修饰的小鼠模型在增殖，分化和肿瘤发生中的作用。我们发现，RB对于巨噬细胞/树突状细胞谱系的分化至关重要，这是支撑胎儿肝脏中红细胞生成的细胞类型。这是一个令人兴奋的小说发现，它将使我们能够剖析最相关的RB-NULL缺陷，以追踪红细胞生成中RB-ID2途径指示的分子事件。我们还将在不存在RB的情况下通过区分ID2和E2F功能来确定ID2在细胞增殖和分化中的靶标特异性。最后，为了确定ID2在通过RB失活引发的肿瘤发生中的作用，我们将使用小鼠模型，其中Rb的突变倾向于垂体癌。这些实验将增加我们对RB促进正常细胞中细胞周期停滞和分化以及这些机制在细胞转化中的扰动的机制的理解。