Constitutive hyperexpression of p21(WAF1) in human U266 myeloma cells blocks the lethal signaling induced by oxidative stress but not by Fas.
p21(WAF1/CIP1) is expressed in a majority of myeloma cells. To investigate the role of p21 in myeloma cell death, comparative studies using two clones of myeloma cells, Fas-sensitive RPMI8226, and Fas-resistant U266 were performed. These latter cells were also resistant to H(2)O(2) up to 100 microM, whereas the former cells were not. SAPK/JNK was found to be a common mediator of RPMI8226 cell death induced by both H(2)O(2) and Fas. Interestingly, the concentrations of H(2)O(2) which activated SAPK/JNK in RPMI8226 cells failed to do so in U266 cells. In contrast, Fas ligation activated SAPK/JNK in both cells almost equally. U266 cells expressed p21 to levels much higher than in RPMI8226 cells. When the p21 levels were reduced using its antisense, H(2)O(2) killed U266 cells by activating SAPK/JNK. However, the reduction in p21 levels neither rendered the U266 cells susceptible to Fas-mediated cell death, nor significantly influenced Fas-induced SAPK/JNK activation. Overall, our data suggest that the p21 hyperexpression in U266 cells blocks the lethal signaling that is induced by H(2)O(2), but not by Fas. The mechanism whereby U266 cells resist Fas-mediated cell death is discussed.
Kim
D K
DK
Laboratory of Cell Biology, Yonsei Medical Research Center, Yonsei University College of Medicine, Seoul 120-752, Korea.
Cho
E S
ES
Lee
S J
SJ
Um
H D
HD
D016923:Cell Death / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019014:fas Receptor; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases