Jun kinase delays caspase-9 activation by interaction with the apoptosome

Thanh H. Tran, Peter Andreka, Claudia O. Rodrigues, Keith A. Webster, Nanette H. Bishopric

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Activation of c-Jun N-terminal kinase 1/2 (JNK) can delay oxidant-induced cell death, but the mechanism is unknown. We found that oxidant stress of cardiac myocytes activated both JNK and mitochondria-dependent apoptosis and that expression of JNK inhibitory mutants accelerated multiple steps in this pathway, including the cleavage and activation of caspases-3 and -9 and DNA internucleosomal cleavage, without affecting the rate of cytochrome c release; JNK inhibition also increased caspase-3 and -9 cleavage in a cell-free system. On activation by GSNO or H2O2, JNK formed a stable association with oligomeric Apaf-1 in a ∼1.4-2.0 mDa pre-apoptosome complex. Formation of this complex could be triggered by addition of cytochrome c and ATP to the cell-free cytosol. JNK inhibition abrogated JNK-Apaf-1 association and accelerated the association of procaspase-9 and Apaf-1 in both intact cells and cell-free extracts. We conclude that oxidant-activated JNK associates with Apaf-1 and cytochrome c in a catalytically inactive complex. We propose that this interaction delays formation of the active apoptosome, promoting cell survival during short bursts of oxidative stress.

Original languageEnglish (US)
Pages (from-to)20340-20350
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number28
DOIs
StatePublished - Jul 13 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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