FMS ONCOGENE--CSF-1 RECEPTOR

逆转录病毒癌基因v-fms是通过遗传途径获得的。 猫白血病病毒(FeLV)与原病毒的重组 来自正常猫细胞的癌基因序列(c-fms)。我们 证实c-fms原癌基因编码一种受体。 单核巨噬细胞集落刺激因子-1 (M-CSF)。到目前为止，这是唯一一个 造血生长因子及其受体都被认为是 进行了克隆和鉴定。C-fms在卵巢癌组织中的高表达 巨噬细胞或在逆转录病毒介导的转移后进入培养 成纤维细胞不会导致转化，而v-FMS 转化成纤维细胞、依赖于CSF-1的巨噬细胞和IL-3- 依赖髓系细胞系。突变的c-fms和 V-fms/c-fms嵌合基因提示两个基因 C-fms的改变需要完全激活其致癌基因 潜在的：(1)基因体内的激活突变， 使受体酪氨酸激酶CSF-1非依赖，和(2) 消除单个C-末端酪氨酸残基(Tyr969)，即 可能是受体的负调控部位 磷酸化。附加嵌合和突变受体 分子将被用来精确定位激活的部位(S) 突变(S)，以鉴定自动磷酸化位点，并确定 蛋白激酶C磷酸化的可能靶位残基 调节受体对佛波酯的下调反应。 脑脊液-1的结构、功能及其转化能力 通过自分泌机制与c-基因共转染细胞 将对FMS基因进行研究。脑脊液-1受体的功能 计划差异化和增殖性回应将是 将c-fms基因导入已提交基因后的评价 体外培养髓系前体细胞。并行方法将评估 V-FMS和CSF-1基因转化早期髓系细胞的能力 祖细胞在体外和体内对白血病的贡献后 基因转移到小鼠造血干细胞。人类 人类染色体上紧密连锁的c-fms和csf-1基因 5q，将评估与以下内容相关的特定重新安排 急性髓系白血病。在基因层面的研究将是 辅以生化方法来识别缺陷 受体功能影响CSF-1诱导的激酶活性， 受体周转和下调。我们的研究很可能会 提供有关正常造血的机制信息和 找出生长因子-受体相互作用中的缺陷 会导致白血病。

The retroviral oncogene, v-fms, was acquired by genetic recombination between a feline leukemia virus (FeLV) and proto- oncogene sequences (c-fms) from normal cat cells. We demonstrated that the c-fms proto-oncogene encodes a receptor for the mononuclear phagocyte colony stimulating factor, CSF-1 (M-CSF). To date, this is the only system in which a hematopoietic growth factor and its receptor have both been cloned and characterized. Expression of c-fms at high levels in macrophages or after retroviral-mediated transfer into cultured fibroblasts does not lead to transformation, whereas v-fms transforms fibroblasts, CSF-1-dependent macrophages, and IL-3- dependent myeloid cell lines. An analysis of mutant c-fms and chimeric v-fms/c-fms genes suggested that two genetic alterations in c-fms are required to fully activate its oncogenic potential: (1) an activating mutation in the body of the gene that renders the receptor tyrosine kinase CSF-1-independent, and (2) elimination of a single C-terminal tyrosine residue (tyr969) that is likely to be a negative regulatory site of receptor phosphorylation. Additional chimeric and mutant receptor molecules will be used to pinpoint the site(s) of activating mutation(s), to identify sites of autophosphorylation, and to define putative target residues for protein kinase C phosphorylation that mediate receptor down modulation in response to phorbol esters. The structure and function of CSF-1 and its ability to transform cells by an autocrine mechanism when cotransfected with the c- fms gene will be studied. The ability of the CSF-1 receptor to program differentiative and proliferative responses will be evaluated after introducing the c-fms gene into committed myeloid precursors in vitro. Parallel approaches will assess the ability of the v-fms and CSF-1 genes to transform early myeloid progenitors in vitro and to contribute to leukemias in vivo after gene transfer into murine hematopoietic stem cells. The human c-fms and CSF-1 genes, both closely linked on human chromosome 5q, will be evaluated for specific rearrangements associated with acute myeloid leukemias. Studies at the genetic level will be complemented by biochemical approaches to identify defects in receptor function affecting CSF-1 induced kinase activity, receptor turnover, and down modulation. Our studies are likely to provide mechanistic information about normal hematopoiesis and to pinpoint defects in growth factor -- receptor interactions that contribute to leukemia.