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J. Biol. Chem., Vol. 282, Issue 28, 20340-20350, July 13, 2007

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Jun Kinase Delays Caspase-9 Activation by Interaction with the Apoptosome^*

Thanh H. Tran¹, Peter Andreka², Claudia O. Rodrigues³, Keith A. Webster, and Nanette H. Bishopric^¶4

From the Departments of Molecular and Cellular Pharmacology, ^¶Medicine and Pediatrics, University of Miami Miller School of Medicine, Miami, Florida 33136

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.

Received for publication, March 14, 2007 , and in revised form, May 3, 2007.

^* This work was supported in part by NHLBI National Institutes of Health Grants R-01-HL71094 (to N. H. B.) and R-01-HL44578 (to K. A. W.) the Fondation Leducq (to N. H. B.) and the Florida Heart Research Institute (to N. H. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Predoctoral fellow of the American Heart Association, Florida Affiliate.

² Present address: Gottsegen Hungarian Institute of Cardiology, 29 Haller Str., H-1096 Budapest, Hungary. Postdoctoral fellow of the American Heart Association, Puerto Rico Affiliate, and recipient of a research award from the George Soros Foundation.

³ Supported by a National Institutes of Health training grant postdoctoral fellowship.

⁴ To whom correspondence should be addressed: Dept. of Molecular and Cellular Pharmacology (R-189), P. O. Box 016189, Miami, FL 33101. Tel.: 305-243-6775; Fax: 305-243-6082; E-mail: n.bishopric{at}miami.edu.

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