Restoration of SHIP-1 activity in human leukemic cells modifies NF-kappaB activation pathway and cellular survival upon oxidative stress.
Nuclear factor-kappa B (NF-kappaB) is an important prosurvival transcription factor activated in response to a large array of external stimuli, including reactive oxygen species (ROS). Previous works have shown that NF-kappaB activation by ROS involved tyrosine phosphorylation of the inhibitor IkappaBalpha through an IkappaB kinase (IKK)-independent mechanism. In the present work, we investigated with more details NF-kappaB redox regulation in human leukemic cells. By using different cell lines (CEM, Jurkat and the subclone Jurkat JR), we clearly showed that NF-kappaB activation by hydrogen peroxide (H2O2) is cell-type dependent: it activates NF-kappaB through tyrosine phosphorylation of IkappaBalpha in Jurkat cells, whereas it induces an IKK-mediated IkappaBalpha phosphorylation on S32 and 36 in CEM and Jurkat JR cells. We showed that this H2O2-induced IKK activation in CEM and Jurkat JR cells is mediated by SH2-containing inositol 5'-phosphatase 1 (SHIP-1), a lipid phosphatase that is absent in Jurkat cells. Indeed, the complementation of SHIP-1 in Jurkat cells made them shift to an IKK-dependent mechanism upon oxidative stress stimulation. We also showed that Jurkat cells expressing SHIP-1 are more resistant to H2O2-induced apoptosis than the parental cells, suggesting that SHIP-1 has an important role in leukemic cell responses to ROS in terms of signal transduction pathways and apoptosis resistance, which can be of interest in improving ROS-mediated chemotherapies.
Gloire
G
G
Virology-Immunology Unit, University of Liège, Liège, Belgium.
Charlier
E
E
Rahmouni
S
S
Volanti
C
C
Chariot
A
A
Erneux
C
C
Piette
J
J
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects*; D005434:Flow Cytometry; D005816:Genetic Complementation Test; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D019169:Jurkat Cells; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C076715:pervanadate; D000072000:NF-KappaB Inhibitor alpha; D014638:Vanadates; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases