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Research ArticleCELLULAR AND MOLECULAR

Ca2+/Calmodulin-Dependent Protein Kinase II and Cytosolic Phospholipase A2 Contribute to Mitogenic Signaling in Myeloblastic Leukemia U-937 Cells

Mubarack M. Muthalif, Farid Ljuca, J. Brent Roaten, Neelu Pentapaty, Mohammed R. Uddin and Kafait U. Malik
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 272-278;
Mubarack M. Muthalif
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Farid Ljuca
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J. Brent Roaten
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Neelu Pentapaty
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Mohammed R. Uddin
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Kafait U. Malik
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Abstract

The signaling mechanisms downstream of growth factor-stimulated proliferation in myeloid leukemia cells have not yet been fully elucidated. Recent evidence suggests that alternate pathways to the mitogen-activated protein kinase cascade are required. We have previously shown that Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) activates cytosolic phospholipase A2 (cPLA2), which is involved in the proliferation of vascular smooth muscle cells. In the present study, the contribution of this pathway was investigated in the proliferation of U-937 myeloid leukemia cells. In U-937 cells, fetal bovine serum (FBS)-induced proliferation was attenuated by CaM kinase II inhibitor KN-93 but not by its inactive analog KN-92. Inhibitors of cPLA2 (methyl arachidonyl fluorophosphonate and arachidonyl trifluoromethyl ketone) also reduced proliferation of U-937 cells. FBS-induced proliferation was also attenuated by cotransfection with cPLA2 antisense oligonucleotides. These results suggest a role for CaM kinase II and cPLA2 in the proliferation of U-937 cells. FBS stimulated CaM kinase II and cPLA2activities in a time-dependent manner. Moreover, FBS-stimulated phosphorylation and activation of cPLA2 activation was inhibited by KN-93. FBS-stimulated phosphorylation of CaM kinase II was blocked by KN-93 but not by cPLA2 inhibitors, suggesting that CaM kinase II activates cPLA2. The products of phospholipid hydrolysis produced by cPLA2, lysophosphatidylcholine but not arachidonic acid, increased [3H]thymidine incorporation in U-937 cells. These data suggest that exposure of U-937 cells to FBS promotes phosphorylation and activation of CaM kinase II, leading to stimulation of cPLA2 and generation of lysophosphatidylcholine and resultant proliferation of these cells.

Footnotes

  • This work was supported by National Institutes of Health Grant 19134-26 (to K.U.M.), an American Heart Association's Beginners grant-in-aid (to M.M.M.), and a Health Sciences fellowship (to N.P.).

  • Abbreviations:
    MAP
    mitogen-activated protein
    ERK
    extracellular regulated kinase
    cPLA2
    cytosolic phospholipase A2
    CaM kinase II
    Ca2+/calmodulin-dependent kinase II
    FBS
    fetal bovine serum
    ATK
    arachidonyl trifluoromethyl ketone
    MAFP
    methyl arachidonyl fluorophosphonate
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    PBS
    phosphate-buffered saline
    BSA
    bovine serum albumin
    PAGE
    polyacrylamide gel electrophoresis
    DMEM
    Dulbecco's modified Eagle's medium
    LPC
    lysophosphatidyl choline
    • Received December 26, 2000.
    • Accepted March 27, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleCELLULAR AND MOLECULAR

Ca2+/Calmodulin-Dependent Protein Kinase II and Cytosolic Phospholipase A2 Contribute to Mitogenic Signaling in Myeloblastic Leukemia U-937 Cells

Mubarack M. Muthalif, Farid Ljuca, J. Brent Roaten, Neelu Pentapaty, Mohammed R. Uddin and Kafait U. Malik
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 272-278;

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Research ArticleCELLULAR AND MOLECULAR

Ca2+/Calmodulin-Dependent Protein Kinase II and Cytosolic Phospholipase A2 Contribute to Mitogenic Signaling in Myeloblastic Leukemia U-937 Cells

Mubarack M. Muthalif, Farid Ljuca, J. Brent Roaten, Neelu Pentapaty, Mohammed R. Uddin and Kafait U. Malik
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 272-278;
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