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Molecular and Cellular Biology, November 2005, p. 9949-9959, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.9949-9959.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of Apoptotic c-Jun N-Terminal Kinase Signaling by a Stabilization-Based Feed-Forward Loop{dagger}

Zhiheng Xu,1,2* Nikolay V. Kukekov,1 and Lloyd A. Greene1

Department of Pathology and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032,1 Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China2

Received 9 August 2005/ Accepted 23 August 2005

A sequential kinase cascade culminating in activation of c-Jun N-terminal kinases (JNKs) plays a fundamental role in promoting apoptotic death in many cellular contexts. The mechanisms by which this pathway is engaged in response to apoptotic stimuli and suppressed in viable cells are largely unknown. Here, we show that apoptotic stimuli increase endogenous cellular levels of pathway components, including POSH, mixed lineage kinases (MLKs), and JNK interacting protein 1, and that this effect occurs through protein stabilization and requires the presence of POSH as well as activation of MLKs and JNKs. Our findings suggest a self-amplifying, feed-forward loop mechanism by which apoptotic stimuli promote the stabilization of JNK pathway components, thereby contributing to cell death.

* Corresponding author. Mailing address: Department of Pathology and Center for Neurobiology and Behavior, Columbia University, 630 W. 168th Street, New York, NY 10032. Phone: (212) 305-6370. Fax: (212) 305-5498. E-mail: zx18{at}columbia.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2005, p. 9949-9959, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.9949-9959.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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