The role of the CSF-1 receptor gene (C-fms) in cell transformation.
The macrophage colony stimulating factor, CSF-1 (M-CSF) exerts its pleiotropic effects on hematopoietic cells of the mononuclear phagocyte series by binding to a single class of high affinity receptors encoded by the c-fms proto-oncogene. Binding of CSF-1 to its receptor activates an intrinsic tyrosine kinase activity, resulting in autophosphorylation of the receptor on tyrosine, rapid receptor down modulation, and phosphorylation of as yet unidentified physiologic substrates that initiate a mitogenic response. Transduction of a human CSF-1 receptor cDNA into mouse fibroblasts enables them to proliferate in response to human recombinant CSF-1, suggesting that the receptor gene contains all the information necessary to elicit a mitogenic response, even in cells which do not normally respond to the growth factor. The v-fms oncogene product has undergone genetic alterations which constitutively activate the receptor kinase in the absence of CSF 1. Insertion of the v-fms gene into macrophage or immature myeloid cell lines abrogates their dependence on hematopoietic growth factors and renders them tumorigenic in nude mice. Reconstitution of lethally irradiated mice with bone marrow stem cells containing the v-fms oncogene also induces clonal proliferation and, ultimately, frank malignancies of multiple hematopoietic lineages. Thus, constitutive activation of the CSF-1 receptor gene, either by mutation or gene rearrangement, might be expected to contribute to leukemia.
Sherr
C J
CJ
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D007938:Leukemia / Q000209:etiology*; D008264:Macrophages; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000209:etiology; D016281:Oncogene Protein gp140(v-fms); D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D016184:Receptors, Colony-Stimulating Factor; D012191:Retroviridae Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
C000715470:MAS1 protein, human; D016281:Oncogene Protein gp140(v-fms); D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D016184:Receptors, Colony-Stimulating Factor; D012191:Retroviridae Proteins; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor