TRANSCRIPTIONAL REGULATION OF THE CSF-1 RECEPTOR GENE

巨噬细胞集落刺激因子的细胞表面受体 (CSF-1或MCSF)由c-fms原癌基因编码，是一种 生长因子受体家族，通过 固有的、配体依赖的酪氨酸特异性蛋白激酶活性。这 提案概述了确定和描述以下机制的研究 调节c-fms原癌基因的转录。CSF-1R主要是 在单核巨噬细胞系细胞上的表达及其承诺 祖细胞、白血病成髓细胞和胎盘滋养层细胞。 初步结果表明，人CSF-1R基因的转录 起源于不同的组织特异性启动子。在建议的 研究，与每个c-fms相关的转录调控序列 启动子将插入氯霉素乙酰转移酶的上游 (CAT)基因，并测试它们在细胞中编程基因表达的能力 恶性胎盘滋养层细胞和髓系细胞系的建立 白血病细胞。关键启动子/增强子序列负责 人单核细胞对CSF-1R表达的转录调控 与与备选方案相关联的类似序列相比 胎盘滋养层细胞使用的转录来源。核蛋白将 通过与细胞因子的相互作用来影响CSF-1R的表达 单核细胞使用的替代启动子/增强子元件和 胎盘滋养层细胞。本提案中概述的研究将提供 对CSF-1R谱系特异性表达的分子基础的洞察 在胎盘发育和正常或异常的造血过程中。他们 也将澄清最近观察到的串联连接 血小板源生长因子B型受体基因和脑脊液-1R基因的表达 人类5号染色体--无论这种定位是纯属巧合还是 促进对CSF-1R表达的新调节。

The cell surface receptor for the macrophage colony stimulating factor (CSF-1 or MCSF) is encoded by the c-fms proto-oncogene and is one of a family of growth factor receptors that triggers mitogenesis through an intrinsic, ligand-dependent tyrosinespecific protein kinase activity. This proposal outlines studies to identify and characterize the mechanisms that regulate transcription of the c-fms proto-oncogene. CSF-1R is primarily expressed on cells of the mononuclear phagocyte lineage and their committed progenitors, by leukemic myeloblasts, and by placental trophoblasts. Preliminary results indicate that transcription of the human CSF-1R gene originates from separate tissue-specific promoters. In the proposed studies, transcriptional regulatory sequences associated with each c-fms promoter will be inserted upstream of the chloramphenicol acetyltransferase (CAT) gene and tested for their ability to program gene expression in cell lines established from malignant placental trophoblasts and myeloid leukemic cells. Critical promoter/enhancer sequences responsible for transcriptional regulation of CSF-1R expression by human monocytes will be compared with analogous sequences associated with an alternative transcription origin used by placental trophoblasts. Nuclear proteins will be identified that influence CSF-1R expression through interaction with the alternative promoter/enhancer elements used by monocytic cells and placental trophoblasts. The studies outlined in this proposal will provide insights into the molecular basis of CSF-1R lineage-specific expression during placental development and normal or aberrant hematopoiesis. They also will clarify the recent observation of tandem linkage between the platelet-derived growth factor B-type receptor gene and the CSF-1R gene on human chromosome 5 - whether this positioning is purely coincidental or promotes novel regulation of CSF-1R expression.