INTERACTION OF ONCOGENES WITH AVIAN CELLS

我们的目标是了解可以调节 多潜能造血干细胞的生长和分化 病毒癌蛋白如何颠覆这些机制而导致白血病。我们的 研究将提供重要的信息，以揭开机制 这些细胞的白血病转化，也将提供 为将这种细胞类型用于基因治疗策略奠定了基础。 终端分化需要整合来自细胞的信号 表面受体和核信号分子。同样，白血病 转化需要在几个基因上发生突变才能发育 一种完全恶性的表型。因此，要理解这些过程， 必须研究信号分子之间的相互作用。模型 正在分析的系统研究具有多潜能的干细胞 分化为髓系细胞和红系细胞的能力 血统。这些细胞可以被来自两个细胞的信号诱导生长 核癌基因v-Ski和内源性c-kit酪氨酸激酶受体。 此外，v-Ski提供的信号与致癌基因的相互作用 酪氨酸激酶v-SEA会导致干细胞白血病。因此，该系统允许 核信号与核信号相互作用的分析 酪氨酸激酶在分化和白血病发生中的作用。 我们的具体目标是： 1.确定v-Ski基因在诱导小鼠卵巢癌中的作用机制。 多潜能细胞的生长。 A)我们将确定v-Ski能够与之相互作用的蛋白质(S)，并 描述复合体的特征；b)我们将确定v-Ski在 自我更新、承诺与多元潜能的差异化 祖细胞。 2.确定生长激活了哪些信号转导通路 酪氨酸激酶因子对肿瘤的生长和分化具有重要作用 多潜能细胞的。 A)我们将确定被激活的路径；b)使用a 不同成分显性负性突变体的组合 信号级联，与v-Sea激酶内的突变一起，我们 将讨论这些途径在成长、承诺和 转型。

Our objectives are to understand the mechanisms that can regulate the growth and differentiation of multipotential hematopoietic stem cells and how viral oncoproteins subvert these mechanisms to cause leukemia. Our studies will provide important information to unravel the mechanisms of the leukemic transformation of these cells, and will also provide the basis for the utilization of this cell type for gene therapy strategies. Terminal differentiation requires the integration of signals from cell surface receptors and nuclear signaling molecules. Similarly, leukemic transformation requires mutations in several genes for the development of a fully malignant phenotype. Thus, to understand these processes the interactions between signaling molecules have to be studied. The model system under analysis studies multipotential stem cells that have the capability to differentiate into cells of the myeloid and erythroid lineages. These cells can be induced to grow by signals from both the nuclear oncogene v-Ski and the endogenous c-kit tyrosine kinase receptor. Furthermore, interaction of signals provided by v-Ski and the oncogenic tyrosine kinase v-Sea cause stem cell leukemia. Thus, this system allows an analysis of the interaction between nuclear signals and signals from tyrosine kinases in both differentiation and leukemogenesis. Our specific aims are: 1. To determine the mechanism of action of the v-Ski gene in inducing the growth of the multipotential cells. a) We will identify the protein(s) that v-Ski can interact with and characterize the complex; b) we will determine the role of v-Ski in the self-renewal, commitment and differentiation of the multipotential progenitor cells. 2. To determine which signal transduction pathways activated by the growth factor tyrosine kinases are important for the growth and differentiation of the multipotential cells. a) We will identify the pathways that are activated; b) using a combination of dominant negative mutants of various components of signaling cascades, together with mutations within the v-Sea kinase, we will address the role of these pathways in growth, commitment and transformation.