c-Jun and the transcriptional control of neuronal apoptosis.
There has been considerable interest in the molecular mechanisms of apoptosis in mammalian neurons because this form of neuronal cell death is important for the normal development of the nervous system and because inappropriate neuronal apoptosis may contribute to the pathology of human neurodegenerative diseases. The aim of recent research has been to identify the key components of the cell death machinery in neurons and understand how the cell death programme is regulated by intracellular signalling pathways activated by the binding of neurotrophins or death factors to specific cell surface receptors. The aim of this commentary was to review research that has investigated the role of the Jun N-terminal kinase (JNK)/c-Jun signalling pathway in neuronal apoptosis, focusing in particular on work carried out with developing sympathetic neurons. Experiments with sympathetic neurons cultured in vitro, as well as with cerebellar granule neurons and differentiated PC12 cells, have demonstrated that JNK/c-Jun signalling can promote apoptosis following survival factor withdrawal. In addition, experiments with Jnk(-/-) knockout mice have provided evidence that Jnk3 may be required for apoptosis in the hippocampus in vivo following injection of kainic acid, an excitotoxin, and that Jnk1 and Jnk2 are required for apoptosis in the developing embryonic neural tube. However, in the embryonic forebrain, Jnk1 and Jnk2 have the opposite function and are necessary for the survival of developing cortical neurons. These results suggest that JNKs and c-Jun are important regulators of the cell death programme in the mammalian nervous system, but that their biological effects depend on the neuronal type and stage of development.
Ham
J
J
Cancer Biology and Molecular Haematology Unit, Camelia Botnar Laboratories, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom. J.Ham@ich.ucl.ac.uk
Eilers
A
A
Whitfield
J
J
Neame
S J
SJ
Shah
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B
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009474:Neurons / Q000166:cytology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics*; D013564:Sympathetic Nervous System / Q000166:cytology; D014158:Transcription, Genetic
D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases