AP-1 proteins in the adult brain: facts and fiction about effectors of neuroprotection and neurodegeneration.
Jun and Fos proteins are induced and activated following most physiological and pathophysiological stimuli in the brain. Only few data allow conclusions about distinct functions of AP-1 proteins in neurodegeneration and neuroregeneration, and these functions mainly refer to c-Jun and its activation by JNKs. Apoptotic functions of activated c-Jun affect hippocampal, nigral and primary cultured neurons following excitotoxic stimulation and destruction of the neuron-target-axis including withdrawal of trophic molecules. The inhibition of JNKs might exert neuroprotection by subsequent omission of c-Jun activation. Besides endogenous neuronal functions, the c-Jun/AP-1 proteins can damage the nervous system by upregulation of harmful programs in non-neuronal cells (e.g. microglia) with release of neurodegenerative molecules. In contrast, the differentiation with neurite extension and maturation of neural cells in vitro indicate physiological and potentially neuroprotective functions of c-Jun and JNKs including sensoring for alterations in the cytoskeleton. This review summarizes the multiple molecular interfunctions which are involved in the shift from the physiological role to degenerative effects of the Jun/JNK-axis such as cell type-specific expression and intracellular localization of scaffold proteins and upstream activators, antagonistic phosphatases, interaction with other kinase systems, or the activation of transcription factors competing for binding to JNK proteins and AP-1 DNA elements.
Herdegen
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Institute of Pharmacology, Hospitalstrasse 4, 24105 Kiel, Germany.
Waetzig
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D000328:Adult; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D051381:Rats; D018808:Transcription Factor AP-1 / Q000502:physiology*
D018696:Neuroprotective Agents; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases