Synaptic activity-mediated suppression of p53 and induction of nuclear calcium-regulated neuroprotective genes promote survival through inhibition of mitochondrial permeability transition.
Cellular stress caused by genetic or environmental factors are considered to be the major inducers of cell death under pathological conditions. Induction of the apoptotic function of the tumor suppressor p53 is a common cellular response to severe genotoxic and oxidative stresses. In the nervous system, accumulation of p53 and increased p53 activity are associated with neuronal loss in acute and chronic neurodegenerative disorders. Here, we show that regulation of the p53 gene (trp53) is an integral part of a synaptic activity-controlled, calcium-dependent neuroprotective transcriptional program. Action potential (AP) bursting suppresses trp53 expression and downregulates key proapoptotic p53 target genes, apaf1 and bbc3 (puma). At the same time, AP bursting activates the nuclear calcium-induced neuroprotective gene, btg2. Depletion of endogenous p53 levels using RNA interference or expression of Btg2 renders neurons more resistant against excitotoxicity-induced mitochondrial permeability transitions and promotes neuronal survival under severe cellular stresses. We propose that suppression of p53 functions together with nuclear calcium-regulated neuroprotective genes in a coordinate and synergistic manner to promote neuronal survival through the stabilization of mitochondria against cellular stresses.
Lau
David
D
Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, Heidelberg, Germany.
Bading
Hilmar
H
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010539:Permeability; D013312:Stress, Physiological / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D002118:Calcium