Regulation of apoptotic c-Jun N-terminal kinase signaling by a stabilization-based feed-forward loop.
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.
Xu
Zhiheng
Z
Department of Pathology and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, 630 W. 168th Street, New York, New York 10032, USA. zx18@columbia.edu
Kukekov
Nikolay V
NV
Greene
Lloyd A
LA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D002166:Camptothecin