TRANSCRIPTIONAL REGULATION OF THE CSF-1 RECEPTOR GENE

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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.