MECHANISMS OF ONCORNAVIRUS INDUCED TRANSFORMATION

冠状病毒诱导转化的机制

基本信息

批准号：
2429624
负责人：
Larry Ray Rohrschneider
金额：
$ 29.41万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-02-01 至 1999-05-31
项目状态：
已结题

项目摘要

Fms is a growth factor receptor regulating monocyte/macrophage growth, development, survival, and function. It also plays a not-well-understood role in placenta development through expression in trophoblast cells. Abnormal Fms expression has been detected in both breast and ovarian tumors where it may play some role in tumor progression or metastases. Macrophage-colony stimulating factor (M-CSF) is the ligand for Fms and is produced by a limited number of cell types including the stromal cells of the bone marrow and uterine epithelial cells. The major aim of this proposed project is to further characterize the control of Fms functions through analysis of positive and negative regulatory signals that mediate and modulate Fms activity. This study will focus on the molecular mechanisms of Fms-induced signal transduction within the hematopoietic environment. One project will further characterize the Fms-specific signal transduction mechanism through analysis of a 150 kDa protein that is rapidly phosphorylated on tyrosine after M-CSF stimulation of Fms- expressing myeloid cells, and becomes associated with other signal transduction molecules (Shc and Grb2). The 150 kDa protein appears to be a unique myeloid cell specific protein unrelated to other known signal transduction proteins, and is not detectable in M-CSF stimulated fibroblast cells expressing Fms. A cDNA encoding the 150 kDa protein will be cloned and the role of this protein in growth and differentiation characterized. A second project will characterize an important negative regulatory mechanism for the control of macrophage development. TGF-beta1 inhibits macrophage development and specifically blocks the Fms-induced expression of the c-myc and bcl-2 genes, but does not affect expression of granulocyte macrophage colony stimulating factor (GM-CSF)-induced c-myc or bcl-2 expression in the same cells. This suggests that M-CSF and GM-CSF induced c-myc and bcl-2 by different mechanisms that could account for the selective growth inhibition of TGF-beta1 on M-CSF-stimulated cells. The molecular mechanism of this selective effect of TGF-beta1 on c-myc and bcl-2 expression will be analyzed using the c-myc promoter coupled to a reporter gene, and the signal transduction pathways from Fms, the GM-CSF receptor and TGF-beta1 receptor culminating in c-myc and bcl-2 induction will be analyzed. These results will help to understand normal hematopoiesis and the multiple steps leading to hematopoietic malignancies.

FMS是调节单核细胞/巨噬细胞生长的生长因子受体，发展，生存和功能。它也扮演着一个不可思议的理解通过在滋养细胞中表达的表达在胎盘发育中的作用。在乳腺和卵巢中都检测到FMS表达异常肿瘤可能在肿瘤进展或转移中起作用。巨噬细胞刺激因子（M-CSF）是FMS的配体，IS 由有限数量的细胞类型产生，包括骨髓和子宫上皮细胞。主要目的拟议的项目是进一步表征FMS功能的控制通过分析介导的正和负调控信号并调节FMS活动。这项研究将集中于分子 FMS诱导的造血内信号转导的机制环境。一个项目将进一步表征FMS特定信号通过分析150 kDa蛋白的转导机制 M-CSF刺激FMS-迅速在酪氨酸上磷酸化表达髓样细胞，并与其他信号相关联转导分子（SHC和GRB2）。 150 kDa蛋白似乎是与其他已知信号无关的独特髓样细胞特异性蛋白转导蛋白，在M-CSF中无法检测到的蛋白质表达FMS的成纤维细胞。编码150 kDa蛋白的cDNA将会克隆和该蛋白质在生长和分化中的作用特征。第二个项目将表征重要的负面控制巨噬细胞发展的调节机制。 TGF-BETA1 抑制巨噬细胞的发展，并专门阻止FMS诱导的 C-Myc和Bcl-2基因的表达，但不影响粒细胞巨噬细胞集落刺激因子（GM-CSF）诱导的C-MYC或 Bcl-2在同一细胞中的表达。这表明M-CSF和GM-CSF 通过不同的机制诱导C-MYC和BCL-2 TGF-BETA1对M-CSF刺激的细胞的选择性生长抑制。这 TGF-BETA1对C-MYC和C-MYC的这种选择性作用的分子机制将使用与A耦合的C-MYC启动子分析Bcl-2的表达报告基因和FMS的信号转导途径，GM-CSF 受体和TGF-BETA1受体在C-MYC和BCL-2诱导中最终将进行分析。这些结果将有助于了解正常造血和导致造血的多个步骤恶性肿瘤。