Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons

Neuroscience. 2005;135(3):781-90. doi: 10.1016/j.neuroscience.2005.05.028. Epub 2005 Aug 19.


The role of p38 and c-jun-N-terminal kinases 1/2, members of the mitogen-activated protein kinase family, in mediating the toxic effects of human immunodeficiency virus-1 transactivator of transcription (Tat) and gp120 were explored in primary mouse striatal neurons in vitro. Both Tat and gp120 caused significant increases in p38 and c-jun-N-terminal kinase mitogen-activated protein kinase phosphorylation, caspase-3 activity, neurite losses and cell death in striatal neurons. Tat-induced increases in caspase-3 activity were significantly attenuated by an inhibitor of c-jun-N-terminal kinase (anthra[1,9-cd]pyrazol-6(2H)-one), but not by an inhibitor of p38 ([4-(4-fluorophenyl)-2-(4-methylsul-finylphenyl)-5-(4-pyridyl)1 H-imidazole]), mitogen-activated protein kinase. However, despite preventing increases in caspase-3 activity, c-jun-N-terminal kinase inhibition failed to avert Tat-induced neuronal losses suggesting that the reductions in caspase-3 activity were insufficient to prevent cell death caused by Tat. Alternatively, gp120-induced increases in caspase-3 activity, neurite losses and neuronal death were prevented by p38, but not c-jun-N-terminal kinase, mitogen-activated protein kinase inhibition. Our findings suggest that gp120 induces neuronal dysfunction and death through actions at p38 mitogen-activated protein kinase, while Tat kills neurons through actions that are independent of p38 or c-jun-N-terminal kinase mitogen-activated protein kinase, or through the concurrent activation of multiple proapoptotic pathways.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cell Size / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Gene Products, tat / pharmacology*
  • HIV Envelope Protein gp120 / pharmacology*
  • HIV-1 / metabolism*
  • MAP Kinase Kinase 4 / metabolism*
  • Mice
  • Mice, Inbred ICR
  • Neostriatum / drug effects
  • Neostriatum / physiology*
  • Nerve Degeneration / physiopathology
  • Neurites / drug effects
  • Neurites / physiology*
  • Neurites / ultrastructure
  • Neurons / drug effects
  • Neurons / physiology*
  • Phosphorylation
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • tat Gene Products, Human Immunodeficiency Virus


  • Gene Products, tat
  • HIV Envelope Protein gp120
  • tat Gene Products, Human Immunodeficiency Virus
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases