Activation of p38 mitogen-activated protein kinase is required for tumor necrosis factor-alpha -supported proliferation of leukemia and lymphoma cell lines.
To elucidate mechanisms of tumor necrosis factor alpha (TNF-alpha)-induced proliferation of a number of human leukemia and lymphoma cell lines, we examined the role of p38 mitogen-activated protein kinase (MAPK) in TNF-alpha signaling in Mo7e and Hut-78 cells. TNF-alpha-dependent p38 MAPK activation was detected in both Mo7e and Hut-78 cells and was blocked by the p38 MAPK inhibitor, SB203580. Ablation of p38 MAPK activity by SB203580 abrogated TNF-alpha-induced Mo7e cell proliferation and TNF-alpha-dependent autocrine growth of Hut-78. As we have shown previously that activation of the nuclear factor kappaB (NF-kappaB) is also required for TNF-alpha-induced Mo7e cell proliferation, the involvement of p38 MAPK in NF-kappaB activation was assessed. SB203580 did not affect TNF-alpha-signaled nuclear translocation and DNA-binding activity of NF-kappaB, and inhibition of NF-kappaB function did not affect TNF-alpha-induced p38 MAPK activation, indicating that these events are not dependent on each other. However, SB203580 depressed the expression of NF-kappaB-dependent genes, as monitored by a kappaB-driven reporter gene. Our findings demonstrate that activation of both p38 MAPK and NF-kappaB plays a critical role in TNF-alpha-mediated survival and proliferation of human leukemia and lymphoma cells, and p38 MAPK acts at least in part by facilitating the transcriptional activation function of NF-kappaB.
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Departments of Internal Medicine, Biochemistry/Molecular Biology and Anatomy, University of South Florida, and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. liur@moffitt.usf.edu
Fan
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Liu
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Olashaw
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Zuckerman
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D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D007938:Leukemia; D008223:Lymphoma; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580