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in p53 null as compared to control wild-type mice. In addition, p53-null
mice display impaired axonal sprouting in the facial motor nuclei of reg-
enerating neurons, which also show reduced expression of Coronin 1b,
GAP-43, and Rab13 (
Di Giovanni et al., 2006; Tedeschi, Nguyen,
Puttagunta, et al., 2009
). Importantly, p53 directly occupies the promoter
of GAP-43 in injured facial motor neurons, driving its expression during
axonal regeneration (
Tedeschi, Nguyen, Puttagunta, et al., 2009
).
Recent data in our laboratory further support a role for p53 in axonal
sprouting and functional recovery in the CNS in a model of spinal cord dorsal
hemisection. In this model, we analyzed motor recovery as well as
corticospinal tract (CST) and serotoninergic axonal sprouting in wild-type
versus p53-null mice and found that physiological recovery of motor function
was impaired in p53-null mice, which showed a more pronounced dieback of
the CST as well as a clear impairment of serotoninergic and CST sprouting.
Moreover, the impairment in CST sprouting could be rescued by p53 gain of
function experiments via viral p53 overexpression in the sensorimotor cortex,
supporting a direct role for p53 in the modulation of the intrinsic neuronal
response of the CST after SCI (
Floriddia, Rathore, Tedeschi, et al., 2012
).
4. EFFECTS OF POSTTRANSLATIONAL MODIFICATIONS
ON p53 FUNCTION
The regulation of p53 expression levels and transcriptional activity
occurs mostly via PTMs that affect p53 stability, nuclear localization, tran-
scriptional recruitment, and promoter occupancy. In this scenario, one of
the most important players is the E3 ligase MDM2, a transcriptional target
of p53 responsible for p53 ubiquitination and degradation and able to inhibit
p53 transcription in a negative autoregulatory loop. p53-MDM2 interaction
is modulated by PTMs such as acetylation of its C-terminus that inhibits
MDM2 binding and p53 inhibition. Indeed, p53 undergoes numerous
PTMs on its N- and C-termini that change its affinity for gene promoters
and affect the binding with other transcription factors and cofactors. p53 ac-
tivity and function are highly tissue and cell type dependent; therefore, the
same pattern of PTMs might have a different biological meaning depending
on the transcriptional and cellular context. The two most common and bet-
ter characterized PTMs affecting p53 are phosphorylation and acetylation.
A kinase cascade phosphorylates p53 on several residues mainly localized
in its N-terminal region including Ser 15, Thr 18, Ser 20, Ser 33, and
Ser 46. Ser 15 phosphorylation in particular leads to p53 stabilization most
