The c-fms proto-oncogene is the transmembrane receptor for the lineage-specific growth factor termed Macrophage-Colony Stimulating Factor (M-CSF, also called CSF-1). This growth factor/receptor combination regulates the growth, survival, and differentiation of committed hematopoietic precursor cells along the macrophage arm of the pathway and, in addition, stimulates differentiated cell functions of mature macrophages. A fully oncogenic version of the M-CSF receptor has been isolated in the form of the v-fms oncogene and the mutations and substitutions responsible for neoplastic activation have been identified. The research proposed in this application will, 1) further characterize and define functional segments of both extracellular and cytoplasmic domains of the normal c-fms growth factor receptor, 2) determine biological functions associated with these segments, and 3) molecularly characterize growth and differentiation signals in terms of transcription and post-transcription regulatory mechanisms. Using molecular biology techniques, subsegments of the murine c-fms gene will be isolated and expressed in either baculovirus, the pZen retroviral expression vector, or as a soluble fusion protein in E. coli with the S. japonicum glutathione S-transferase protein. The M-CSF binding """"""""pocket"""""""" will be defined and Immunoglobulin-like domains regulating potential M-CSF-induced conformational changes and intracellular transport will be examined. Regions of the murine c-fms gene regulating growth and differentiation will be defined by mutational analysis with functional assays in vitro and in vivo using murine bone marrow cells and lines that exhibit c-fms induced growth and differentiation. Finally, the growth and differentiation signals will be related to transcriptional activation of known genes as well as new ones identified by differential hybridization techniques. These results will help to understand normal hematopoiesis and mechanisms that lead to the development of hematopoietic malignancies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Fred Hutchinson Cancer Research Center
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