The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling.
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 SCF(Fbw7), ... 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. SCF(Fbw7) therefore antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling, allowing neurons to tolerate potentially neurotoxic JNK activity.
Mesh Terms:
Amino Acid Sequence, Animals, Apoptosis, Base Sequence, Cell Cycle Proteins, Cell Line, F-Box Proteins, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Neurons, PC12 Cells, Phosphorylation, Proto-Oncogene Proteins c-jun, RNA, Small Interfering, Rats, Transcription Factor AP-1, Transfection, Ubiquitin, Ubiquitin-Protein Ligases
Amino Acid Sequence, Animals, Apoptosis, Base Sequence, Cell Cycle Proteins, Cell Line, F-Box Proteins, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Neurons, PC12 Cells, Phosphorylation, Proto-Oncogene Proteins c-jun, RNA, Small Interfering, Rats, Transcription Factor AP-1, Transfection, Ubiquitin, Ubiquitin-Protein Ligases
Science
Date: Feb. 27, 2004
PubMed ID: 14739463
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