Macrophage-colony-stimulating factor (CSF-1) induces proliferation, chemotaxis, and reversible monocytic differentiation in myeloid progenitor cells transfected with the human c-fms/CSF-1 receptor cDNA.
The c-fms protooncogene encodes the receptor for macrophage-colony-stimulating factor (CSF-1). Expression vectors containing either normal or oncogenic point-mutated human c-fms genes were transfected into interleukin 3 (IL-3)-dependent 32D cells in order to determine the effects of CSF-1 signaling in this murine clonal myeloid progenitor cell line. CSF-1 was shown to trigger proliferation in association with monocytic differentiation of the 32D-c-fms cells. Monocytic differentiation was reversible upon removal of CSF-1, implying that CSF-1 was required for maintenance of the monocyte phenotype but was not sufficient to induce an irrevocable commitment to differentiation. Human CSF-1 was also shown to be a potent chemoattractant for 32D-c-fms cells, suggesting that CSF-1 may serve to recruit monocytes from the circulation to tissue sites of inflammation or injury. Although c-fms did not release 32D cells from factor dependence, point-mutated c-fms[S301,F969] (Leu-301----Ser, Tyr-969----Phe) was able to abrogate their IL-3 requirement and induce tumorigenicity. IL-3-independent 32D-c-fms[S301,F969] cells also displayed a mature monocyte phenotype, implying that differentiation did not interfere with progression of these cells to the malignant state. All of these findings demonstrate that a single growth factor receptor can specifically couple with multiple intracellular signaling pathways and play a critical role in modulating cell proliferation, differentiation, and migration.
Pierce
J H
JH
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
Di Marco
E
E
Cox
G W
GW
Lombardi
D
D
Ruggiero
M
M
Varesio
L
L
Wang
L M
LM
Choudhury
G G
GG
Sakaguchi
A Y
AY
Di Fiore
P P
PP
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects*; D003115:Colony-Stimulating Factors / Q000378:metabolism / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011956:Receptors, Cell Surface / Q000502:physiology*; D014162:Transfection
D003115:Colony-Stimulating Factors; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor