Role of p70 S6 kinase in cytokine-regulated hemopoietic cell survival.
The signalling mechanisms required for cell survival remain relatively undefined. We and others have shown that phosphatidylinositol 3-kinase (PI 3-kinase) is an important enzyme in the prevention of apoptosis, and this property is independent of p21ras-MAP kinase activation. It is therefore important to define the downstream targets of this enzyme mediating the inhibition of apoptosis. We report here than p70 S6 kinase, a protein critical for progression through the cell cycle and a downstream effector of PI 3-kinase, is not required for the survival of cytokine-stimulated human T-cells or murine mast cells. The potent inhibitor of p70 S6 kinase activation, rapamycin, was unable to induce apoptosis in cells stimulated with cytokines. As well, PI 3-kinase inhibitors that also blocked the activation of p70 S6 kinase were able to induce apoptosis. These studies, therefore, describe a bifurcation of signalling pathways from PI 3-kinase leading to different physiological outcomes.
Scheid
M P
MP
Department of Medicine, University of British Columbia, Jack Bell Research Centre, Vancouver, Canada.
Charlton
L
L
Pelech
S L
SL
Duronio
V
V
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000201:enzymology
D016207:Cytokines; D004791:Enzyme Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007378:Interleukins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus