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: 6782355
• 负责人: ANNA LASORELLA
• 金额: $ 36.38万
• 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/6782355
• 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）肿瘤抑制蛋白对执行细胞周期终止、完全分化和确保细胞存活至关重要。在缺乏Rb的情况下，小鼠发育受损，Rb突变胚胎在妊娠中期死亡，红细胞生成和神经发生严重缺陷。螺旋环螺旋蛋白分化抑制剂2 （Id2）协调增殖和分化。Id2结合Rb并拮抗其抗增殖功能。我们最近报道了切除小鼠Id2基因可以挽救rb突变胚胎的表型异常和致死率。这些结果表明Id2是肿瘤抑制蛋白的相关靶点，其功能在发育过程中必须受到Rb的抑制。这项工作的长期目标是利用转基因小鼠模型了解Rb-Id2复合物在增殖、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，而巨噬细胞/树突状细胞谱系是一种支持胎儿肝脏红细胞生成的细胞类型。这是一个令人兴奋的新发现，将使我们能够解剖最相关的Rb-null缺陷，以追踪红细胞生成过程中Rb-Id2途径指导的分子事件。我们还将通过区分Rb缺失情况下Id2和E2F的功能来确定Id2在细胞增殖和分化中的靶特异性。最后，为了确定Id2在Rb失活引发的肿瘤发生中的作用，我们将使用Rb突变易导致垂体癌的小鼠模型。这些实验将增加我们对Rb在正常细胞中促进细胞周期阻滞和分化的机制以及这些机制在细胞转化中的扰动的理解。