Intracellular Supplies of Guanine Ribonucleotides Regulate the Responsiveness of Human Myeloid Progenitors to GM-CSF
Abstract
Induced maturation of the human myeloid leukemia cell line, HL-60, is associated with a down-regulation of guanine ribonucleotide (G-NTD) synthesis from inosine monophosphate (IMP) and with depletion of GTP and GDP pools. Inhibitors of IMP-dehydrogenase (e.g. tiazofurin and mycophenolic acid), which block G-NTD synthesis from IMP, are potent inducers of maturation, while exogenous guanosine prevents induced maturation the promotes cell proliferation to the extent that high G-NTD levels are maintained. These findings prompted us to examine the possibility that guanylate depletion and repletion may affect a GTP-regulated signal transduction pathway for myelopoietic growth factors, Recombinant human GM-CSF stimulates the proliferation of HL-60 cells in serum- free suspension culture and in clonal assays. These effects are enhanced by guanosine but blocked by the IMP-dehydrogenase inhibitor, tiazofurin. At concentrations of 1.0 - 5.0 nM, rhGM-CSF may also be shown to stimulate phospholipase C mediate hydrolysis of PIP2 and to cause rapid, transient increases in cytosolic free Ca(2+) in HL-60 cells. These effects are also blocked by pretreatment of cells with tiazofurin. We conclude from these studies that intracellular G-NTD supplies may influence the growth and maturation of primitive myeloid progenitors in part by affecting early, GTP-regulated steps in signal-response coupling for myelopoietic growth factors. Reprints.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 1987
- Accession Number
- ADA200138
Entities
People
- D. B. Kuhns
- D. G. Wright
- Marti Jett
- V. F. Larussa
Organizations
- Walter Reed Army Institute of Research