Cell proliferation in hematopoiesis

描述(申请人提供)：控制细胞增殖是发展中的一个中心主题。细胞在器官形成过程中经历的分裂数量如何有限还不是很清楚，但众所周知，控制增殖的机制在人类和果蝇中是保守的。果蝇淋巴腺和血细胞的形成和成熟所必需的大多数基因在人类中都是保守的。Toll-NF：B、JAK/STAT、Notch和Ras/Raf等途径调控脊椎动物的造血和果蝇的淋巴腺发育。我们已经确定的一种基因控制着细胞经历的分裂数量。它的蛋白质(Zfrp8)与人类蛋白质(PDCD2)有50%的相似性。苍蝇zfrp8/PDCD2突变体最明显的表型是造血器官淋巴腺大量过度生长，伴随着幼虫发育的延迟。我们发现，zfrp8通过控制细胞增殖而不是细胞凋亡来调节淋巴腺的生长。我们的结果表明，zfrp8调节果蝇体内的Stat水平。Zfrp8的缺失导致了类似于JAK/STAT通路中功能获得突变的表型。PDCD2似乎参与了人类的造血，并以两种主要形式存在于人体组织中。在骨髓中，我们检测到一种更大形式的蛋白质，这种蛋白质富含在含有干细胞的部分中。一种较小形式的蛋白质存在于白细胞中，几乎检测不到数量。在白血病患者的骨髓和血液中，都存在高水平的较小形式的PDCD2。我们计划确定zfrp8在果蝇正常淋巴腺和血细胞发育中的作用，以及在其他组织生长中的作用，并确定其分子功能。使用各种方法，我们将寻找与zfrp8一起起作用的其他基因。进一步，我们将确定脊椎动物中PDCD2的基因产物，并将利用血液干细胞和组织培养细胞的体外分化来研究它们在人类造血细胞增殖中的作用。

DESCRIPTION (provided by applicant): Control of cell proliferation is a central theme in development. How the number of divisions a cell undergoes during organ formation is limited is not well understood, but it is known that the mechanisms controlling proliferation are conserved in humans and Drosophila. And most genes essential for the formation and maturation of the Drosophila lymph gland and hemocytes are conserved in humans. Pathways such as Toll-NF:B, JAK/STAT, Notch, and Ras/Raf regulate hematopoiesis in vertebrates and lymph gland development in flies. A gene we have identified controls the number of divisions a cell undergoes. Its protein (Zfrp8) is >50% similar to the human protein (PDCD2). The most obvious phenotype of fly zfrp8/PDCD2 mutants is a massive overgrowth of the hematopoietic organ, the lymph gland, accompanied by a delay in larval development. We have found that zfrp8 regulates lymph gland growth by controlling cell proliferation and not apoptosis. Our results suggest that zfrp8 regulates Stat levels in Drosophila. Loss of zfrp8 results in a similar phenotype to gain-of-function mutations in the JAK/STAT pathway. PDCD2 appears to be involved in human hematopoiesis and is present in human tissues in two major forms. In bone marrow we detect a larger form of the protein that is enriched in a fraction containing stem cells. A smaller form of the protein is present in barely detectable amounts in white blood cells. In both the bone marrow and blood of leukemia patients, high levels of the smaller form of PDCD2 are present. We plan to define the role of zfrp8 in Drosophila in normal lymph gland and hemocyte development, and in growth of other tissues and to identify its molecular function. Using a variety of approaches we will search for additional genes functioning with zfrp8. Further, we will define the gene products of PDCD2 in vertebrates, and will investigate their function in cell proliferation in human hematopoiesis using in vitro cell differentiation of blood stem cells and tissue culture cells.