Synergistic induction of phospholipid metabolism by granulocyte-macrophage colony stimulating factor and steel factor in human growth factor-dependent cell line, M07e.
Steel factor (SLF), the ligand for the c-kit proto-oncogene tyrosine kinase receptor, synergizes with several hematopoietic growth factors to produce greatly enhanced proliferation of normal human hematopoietic progenitor cells as well as that of the human growth factor-dependent myeloid cell line, M07e. The mechanisms of this phenomenon remain unknown. In an attempt to understand the cellular processes relevant to this phenomenon, we examined the effects of SLF and granulocyte-macrophage colony-stimulating factor (GM-CSF) on induced lipid metabolism in M07e cells. We find that both GM-CSF and SLF induced increased phosphatidylcholine (PC) turnover rates (biosynthesis and degradation) as measured by increased [3H]-choline labelling, with SLF being more potent than GM-CSF after 6 h of stimulation, but equipotent at 24 h of stimulation. The labelling of aqueous intermediates of PC metabolism was also increased by cytokine stimulation, most notably phosphocholine. Simultaneous stimulation with GM-CSF plus SLF resulted in a true synergistic induction of PC, lysoPC, and phosphocholine labelling. GM-CSF and SLF each induced asymmetric labelling of various phospholipid classes as measured by incorporation of different [3H]-fatty acids. [3H]-myristic acid labelling of phosphatidylserine was most prominently induced (approximately 12-fold). Cytosolic choline kinase activity was also upregulated more than twofold over control by SLF, which might contribute to the increased phosphocholine labelling. These effects may have relevance to the intracellular mechanisms of the synergistic proliferative stimulation of SLF plus GM-CSF on M07e cells.
Mantel
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Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis 46202-5121, USA.
Luo
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Broxmeyer
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HE
D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000378:metabolism; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute; D019814:Myristic Acid; D009227:Myristic Acids / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D019089:Stem Cell Factor / Q000494:pharmacology*; D013997:Time Factors; D014316:Tritium; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D009227:Myristic Acids; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D010743:Phospholipids; D000090063:Proto-Oncogene Mas; D019089:Stem Cell Factor; D019814:Myristic Acid; D014316:Tritium; D016718:Arachidonic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002797:Choline Kinase; D002794:Choline