Di Giovanni et al., who previously identified a group of temporally correlated genes that appear after spinal cord injury, including some known to be involved in neurite outgrowth and axon regeneration, undertook a search for a transcription factor that might coordinately regulate their expression. In silico promoter analysis revealed that two of these genes, the gene encoding the actin-binding Coronin 1b and the small guanosine triphosphatase Rab13 (both implicated in neurite outgrowth), had multiple binding sites for the transcription factor p53. Chromatin immunoprecipitation (ChIP) analysis confirmed that p53 bound to the Coronin 1b and Rab13 promoters, and p53 expression enhanced expression of their mRNA and protein in various cell lines. In cultured rat cortical neurons exposed to neuronal medium or PC12 cells exposed to nerve growth factor, nuclear p53 abundance increased together with expression of Coronin 1b and Rab13 during neurite outgrowth, whereas a p53 dominant negative inhibited Coronin 1b and Rab13 expression and neurite outgrowth. In NT2/D1 human teratocarcinoma cells, which develop neurites and synapses in response to treatment with retinoic acid (RA), RA stimulated acetylation of p53 at lysine 320. ChIP analysis and experiments involving p53 acetylation mutants indicated that p53 acetylated at lysine 320 binds to the Coronin 1b and Rab13 promoters to stimulate Coronin 1b and Rab13 expression and neurite outgrowth. Mice lacking p53 showed decreased nerve regeneration after axotomy compared with wild-type mice and, unlike regenerating neurons in wild-type mice, those in p53-null mice did not show enhanced expression of Coronin 1b and Rab13. Thus, the authors conclude that the well-known tumor suppressor p53, already implicated in neuronal apoptosis, likely plays a role in stimulating neurite outgrowth and neuronal regeneration.
S. Di Giovanni, C. D. Knights, M. Rao, A. Yakovlev, J. Beers, J. Catania, M. L. Avantaggiati, A. I. Faden, The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration. EMBO J. 25, 4084-4096 (2006). [PubMed]