Modulation of nitric oxide-induced apoptotic death of HL-60 cells by protein kinase C and protein kinase A through mitogen-activated protein kinases and CPP32-like protease pathways

Cell Immunol. 1999 May 25;194(1):36-46. doi: 10.1006/cimm.1999.1480.


To define the signaling pathways during NO-induced apoptotic events and their possible modulation by two protein kinase systems, we explored the involvement of three structurally related mitogen-activated protein kinase subfamilies. Exposure of HL-60 cells to sodium nitroprusside (SNP) strongly activated p38 kinase, but did not activate c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). In addition, SNP-induced apoptosis was markedly blocked by the selective p38 kinase inhibitor (SB203580) but not by MEK1 kinase inhibitor (PD098059), indicating that p38 kinase serves as a mediator of NO-induced apoptosis. In contrast, treatment of cells with phorbol 12-myristate 13-acetate (PMA) strongly activated not only JNK but also ERK, while not affecting p38 kinase. However, although SNP by itself weakly activated CPP32-like protease, SNP in combination with PMA markedly increased the extent of CPP32-like protease activation. Interestingly, N6,O2-dibutylyl cAMP (DB-cAMP) significantly blocked SNP- or SNP plus PMA-induced activation of CPP32-like protease and the resulting induction of apoptosis. DB-cAMP also blocked PMA-induced JNK activation. Collectively, these findings demonstrate the presence of specific up- or down-modulatory mechanisms of cell death pathway by NO in which (1) p38 kinase serves as a mediator of NO-induced apoptosis, (2) PKC acts at the point and/or upstream of JNK and provides signals to potentiate NO-induced CPP32-like protease activation, and (3) PKA lies upstream of either JNK or CPP32-like protease to protect NO- or NO plus PMA-induced apoptotic cell death in HL-60 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Bucladesine / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Caspase 3
  • Caspases / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Enzyme Activation
  • HL-60 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Mitogens / pharmacology
  • Nitric Oxide / metabolism*
  • Nitroprusside / pharmacology
  • Protein Kinase C / metabolism*
  • Signal Transduction*
  • Tetradecanoylphorbol Acetate / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • p38 Mitogen-Activated Protein Kinases


  • Mitogens
  • Nitroprusside
  • Nitric Oxide
  • Bucladesine
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Tetradecanoylphorbol Acetate