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Science 303 (5662): 1374-1378

Copyright © 2004 by the American Association for the Advancement of Science

The Ubiquitin Ligase SCFFbw7 Antagonizes Apoptotic JNK Signaling

Abdolrahman S. Nateri, Lluís Riera-Sans, Clive Da Costa, Axel Behrens*

Abstract: Jun N-terminal kinases (JNKs) are essential for neuronal microtubule assembly and apoptosis. Phosphorylation of the activating protein 1 (AP1) transcription factor c-Jun, at multiple sites within its transactivation domain, is required for JNK-induced neurotoxicity. We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCFFbw7, which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation. Fbw7 depletion resulted in accumulation of phosphorylated c-Jun, stimulation of AP1 activity, and neuronal apoptosis. SCFFbw7 therefore antagonizes the apoptotic c-Jun–dependent effector arm of JNK signaling, allowing neurons to tolerate potentially neurotoxic JNK activity.

Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.

* To whom correspondence should be addressed. E-mail: axel.behrens{at}cancer.org.uk

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