The C-terminal cytoplasmic region of the granulocyte colony-stimulating factor receptor mediates apoptosis in maturation-incompetent murine myeloid cells.
Granulocyte colony-stimulating factor (G-CSF) promotes the survival and proliferation of myeloid progenitors and induces maturation of these cells toward terminally differentiated neutrophils. Using transfectants of the murine IL-3-dependent myeloid cell line 32D that express the human G-CSF receptor (32D/WT cells), we show here that G-CSF can also exert adverse effects on myeloid cell survival. Although initially enhancing IL-3-driven proliferation of 32D/WT cells, G-CSF strongly inhibited cell survival at later stages of culture. The loss of viability of 32D/WT cells following sustained G-CSF stimulation was not accompanied by progressive neutrophilic maturation. Instead, 32D/WT cells exhibited features characteristic of apoptosis. The apoptosis-inducing effect of G-CSF was seen at concentrations of IL-3 that could support long-term proliferation and survival of 32D/WT cells in the absence of G-CSF. Experiments with 32D cells expressing mutant forms of the G-CSF receptor revealed that the death signals were mediated exclusively through the membrane-distal cytoplasmic part of the G-CSF receptor, a region also involved in maturation signaling.
Dong
F
F
Department of Hematology, The Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Pouwels
K
K
Hoefsloot
L H
LH
Rozemuller
H
H
Löwenberg
B
B
Touw
I P
IP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009195:Peroxidase / Q000032:analysis; D017434:Protein Structure, Tertiary; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D015415:Biomarkers; D007377:Interleukin-3; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase