p53 in neuronal apoptosis.
The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 can trigger apoptosis in many cell types including neurons. Apoptosis is a form of programmed cell death that occurs in neurons during development of the nervous system and may also be responsible for neuronal deaths that occur in neurological disorders such as stroke, and Alzheimer's and Parkinson's diseases. p53 production is rapidly increased in neurons in response to a range of insults including DNA damage, oxidative stress, metabolic compromise, and cellular calcium overload. Target genes induced by p53 in neurons include those encoding the pro-apoptotic proteins Bax and the BH3-only proteins PUMA and Noxa. In addition to such transcriptional control of the cell death machinery, p53 may more directly trigger apoptosis by acting at the level of mitochondria, a process that can occur in synapses (synaptic apoptosis). Preclinical data suggest that agents that inhibit p53 may be effective therapeutics for several neurodegenerative conditions.
Culmsee
Carsten
C
Department Pharmazie, Pharmazeutische Biologie-Biotechnologie, Ludwig-Maximilians-Universität, München, Germany. ccuph@cup.uni-muenchen.de
Mattson
Mark P
MP
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2; D013569:Synapses / Q000502:physiology; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; D009687:Nuclear Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2