Biological consequences of a point mutation at codon 969 of the FMS gene.
The FMS proto-oncogene encodes the cell surface receptor for colony stimulating factor-1 (CSF-1). Mutations of the FMS gene at codon 969, in the C-terminal region of the gene, have been detected in haematological malignancies. To ascertain the biological significance of a mutation at this codon, we have used a murine haematopoietic cell line, FDC-P1, containing a mutation at codon 969 that results in a phenylalanine replacing a tyrosine. FMS 969 mutant cells and v-fms transfected cells conferred interleukin 3 (IL-3) independent stimulation of FDC-P1 cells, whereas cells transfected with a wild-type FMS construct required exogenous IL-3 for growth. FDC-P1 cells containing a FMS 969 mutation and v-fms transfected cells were tumorigenic in nude mice. Binding studies with radioidonated CSF-1 revealed saturable specific binding in FMS wild-type cells with a Km of 0.9 mM; however, mutant FMS-containing cells did not display saturation kinetics, but instead exhibited a linear relationship between ligand concentration and amount bound. Constitutive expression of FOS was detected in 969 mutant cells in the absence of exogenous CSF-1, a phenotype that was only inducible in wild-type cells in response to CSF-1. FOS and JUNB expression by v-FMS transfected cells showed a similar pattern to FMS wild-type cells. This mutation has been detected in patients with haematological malignancies, and illustrates that the pathway of FMS 969 phenylalanine mutations and v-fms induced pathogenesis can be distinguished. These data indicate that there is a biological role for FMS codon 969 phenylalanine mutation which results in transformation of FDC-P1 cells.
School of Biomedical Sciences, University of Ulster at Coleraine, N. Ireland, UK. H.McGlynn@ulst.ac.uk
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D000818:Animals; D015152:Blotting, Northern; D015197:Carcinogenicity Tests; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003062:Codon / Q000235:genetics*; D016236:Genes, fms / Q000235:genetics*; D016762:Genes, fos / Q000187:drug effects / Q000235:genetics; D016758:Genes, jun / Q000187:drug effects / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology; D007377:Interleukin-3 / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D017354:Point Mutation / Q000235:genetics* / Q000502:physiology*; D012313:RNA / Q000032:analysis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis
D003062:Codon; D007377:Interleukin-3; D007457:Iodine Radioisotopes; D012313:RNA; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor