Role of the p70 S6 kinase cascade in neutrophilic differentiation and proliferation of HL-60 cells-a study of transferrin receptor-positive and -negative cells obtained from dimethyl sulfoxide- or retinoic acid-treated HL-60 cells.
Previously, we suggested that p70 S6 kinase (p70 S6K) plays an important role in the regulation of neutrophilic differentiation of HL-60 cells; this conclusion was based on our analysis of transferrin receptor (Trf-R) positive (Trf-R(+)) and negative (Trf-R(-)) cells that appeared after treatment with dimethyl sulfoxide (Me(2)SO). In this study, we analyzed the upstream of p70 S6K in relation to the differentiation and proliferation of both cell types. The granulocyte colony-stimulating factor (G-CSF)-induced enhancement of phosphatidylinositol 3-kinase (PI3K) activity in Trf-R(+) cells was markedly higher than that in Trf-R(-) cells. Wortmannin, a specific inhibitor of PI3K, partially inhibited G-CSF-induced p70 S6K activity and G-CSF-dependent proliferation, whereas rapamycin, an inhibitor of p70 S6K, completely inhibited these activities. The wortmannin-dependent enhancement of neutrophilic differentiation was similar to that induced by rapamycin. From these results, we conclude that the PI3K/p70 S6K cascade may play an important role in negative regulation of neutrophilic differentiation in HL-60 cells. For the G-CSF-dependent proliferation, however, p70 S6K appears to be a highly important pathway through not only a PI3K-dependent but also possibly an independent cascade.
Kanayasu-Toyoda
Toshie
T
Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-Ku, Tokyo 158-8501, Japan.
Yamaguchi
Teruhide
T
Oshizawa
Tadashi
T
Kogi
Mieko
M
Uchida
Eriko
E
Hayakawa
Takao
T
D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D002465:Cell Movement; D002469:Cell Separation; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011990:Receptors, Transferrin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases; D010100:Oxygen; D020123:Sirolimus; D000077191:Wortmannin; D004121:Dimethyl Sulfoxide