Bad as a converging signaling molecule between survival PI3-K/Akt and death JNK in neurons after transient focal cerebral ischemia in rats

J Cereb Blood Flow Metab. 2007 Mar;27(3):521-33. doi: 10.1038/sj.jcbfm.9600367. Epub 2006 Jul 5.


Bad, a proapoptotic Bcl-2 family protein, plays a critical role in determining cell death/survival. The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway and the c-Jun N-terminal kinase (JNK) pathway are thought to be involved in regulation of Bad. Therefore, the present study was performed to clarify the role of Bad as a common target of the PI3-K/Akt and JNK pathways after transient focal cerebral ischemia (tFCI) in rats. We found that Akt activity increased at 3 h and then decreased, whereas JNK activity increased 7 to 24 h in the peripheral area after tFCI. Administration of LY294002, a PI3-K-specific inhibitor, exacerbated DNA fragmentation, whereas administration of SP600125, a JNK-specific inhibitor, attenuated it. Inhibited by LY294002, phospho-Bad (Ser136) expression increased in the peripheral area 3 h after tFCI, with suppression of Akt activity. Furthermore, phospho-Bad (Ser136) and phospho-Akt (Ser473) were colocalized. Decreases in phospho-Bad (Ser136) and Bad/14-3-3 dimerization and increases in Bcl-X(L)/Bad or Bcl-2/Bad dimerization observed 7 to 24 h after tFCI, were prevented by SP600125 administration, with inhibition of JNK activity. The present study indicates that signal predominance varies from PI3-K/Akt-mediated survival signaling to JNK-mediated death signaling with the development of neuronal damage in the peripheral area after tFCI. This study also suggests that PI3-K/Akt has a role in Bad inactivation, whereas the JNK pathway is involved in Bad activation. We conclude that Bad may be an integrated checkpoint of PI3-K/Akt-mediated survival signaling and JNK-mediated death signaling and that it contributes to cell fate in the peripheral area after cerebral ischemia.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Survival
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Antibody Technique
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Nick-End Labeling
  • Ischemic Attack, Transient / metabolism*
  • Ischemic Attack, Transient / pathology
  • MAP Kinase Kinase 4 / metabolism*
  • Male
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • bcl-Associated Death Protein / metabolism*


  • Bad protein, rat
  • Enzyme Inhibitors
  • bcl-Associated Death Protein
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 4