The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration

Abstract

Axon regeneration is substantially regulated by gene expression and cytoskeleton remodeling. Here we show that the tumor suppressor protein p53 is required for neurite outgrowth in cultured cells including primary neurons as well as for axonal regeneration in mice. These effects are mediated by two newly identified p53 transcriptional targets, the actin-binding protein Coronin 1b and the GTPase Rab13, both of which associate with the cytoskeleton and regulate neurite outgrowth. We also demonstrate that acetylation of lysine 320 (K320) of p53 is specifically involved in the promotion of neurite outgrowth and in the regulation of the expression of Coronin 1b and Rab13. Thus, in addition to its recognized role in neuronal apoptosis, surprisingly, p53 is required for neurite outgrowth and axonal regeneration, likely through a different post-translational pathway. These observations may suggest a novel therapeutic target for promoting regenerative responses following peripheral or central nervous system injuries.

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

“…However, recent experimental evidence 32 and our own work using HDAC class I and HDAC class I and II inhibitors 33 has proven this to be insufficient in producing postlesion regeneration of sensory fibres following a spinal or optic nerve injury and therefore unlikely the key to unlocking the molecular mechanisms of regeneration. While our work here describes that specific epigenetic codes are induced endogenously following a conditioning lesion that leads to CNS regeneration, it is also consistent with previous findings from our laboratory that showed the presence of a transcriptional complex formed by p53, p300 and PCAF in the proximity of several RAGs including GAP-43, Coronin 1b and Rab13 in primary neurones as well as facial motor neurones in a PNS facial nerve axotomy model [34][35][36] . Additionally, we found that the histone acetyltransferase p300 (which may form a complex with PCAF) is developmentally regulated in retinal ganglion cells and whose overexpression drives axonal regeneration of the injured optic nerve 33 .…”

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

“…Notably, CORO1B protein levels increased after IR in wild type thymocytes but remained essentially unchanged in mutant thymocytes. The loss of increase in protein level is consistent with a recent study showing CORO1B to be induced by p53 in neuronal outgrowth only when Lys-320 was acetylated (46). Furthermore, p53 induces expression of EGFR (47), and EGFR regulates the expression of ACTN3 and USP14, two proteins that increased in expression in the mutant but not significantly in the wild type (48).…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…The abnormal regulation of p53 has been observed in ALS patients [134], and cellular and animal ALS models [135,136]. Interestingly, p53 acetylation at K320 through p300/CBP and PCAF serves as a prosurvival signal, and promotes neurite outgrowth and neuronal maturation [137]. Activating HAT activity in ALS motor neurons might mediate p53 K320 acetylation and facilitate targeting toward pro-survival rather than pro-apoptotic functions.…”