Gatekeeper Between Quiescence and Differentiation: p53 in Axonal Outgrowth and Neurogenesis - International Review of Neurobiology - page 80

likely by disrupting its interaction with MDM2, preventing its nuclear ex-
port, and favoring p53 acetylation and activation ( Murray-Zmijewski et al.,
2008 ).
Acetylation has been linked to an increase in the activity of p53, and it
occurs in two different regions of p53 C-terminal region; in neurons, it is
mediated mostly by CBP/p300 and P/CAF histone acetyltransferases
( Brooks & Gu, 2003 ). Specifically, P/CAF is responsible for the acetylation
of the lysine 320 and CBP/p300 is instead required for the acetylation of the
Lys 370, 372, 373, and 382 ( Avantaggiati et al., 1997; Lill, Grossman,
Ginsberg, DeCaprio, & Livingston, 1997; Liu et al., 1999 ).
Importantly, neurotrophin signaling is able to enhance different types of
PTMs on p53, leading to an increase of its activity on specific gene pro-
moters. For instance, in neurons, NGF administration induces a kinase cas-
cade that leads to p38 MAPK-dependent phosphorylation and subsequently
to p53 activation, including at Ser 15 and Ser 48, enhancing its transcrip-
tional activity ( Zhu, Mao, Sun, Xia, & Greenberg, 2002 ). In neuronal cell
lines such as PC-12 and neuroblastoma cells, NGF and retinoic acid admin-
istration stimulate PCAF-mediated acetylation of p53 at Lys 320, increasing
its transcriptional activity and selectivity for certain specific promoters,
including for the axonal outgrowth genes Coronin 1b and Rab13
( Di Giovanni et al., 2006; Wong et al., 2004 ). Accordingly, the
expression level of p53 acetylated at Lys 320 and 373 is enhanced during
neuronal maturation and outgrowth in primary cortical neurons
( Tedeschi, Nguyen, Puttagunta, et al., 2009 ). In primary cultures of
cerebellar and cortical neurons, overexpression of a mutant form of p53
that mimics constitutive acetylation via lysine to glutamine transition (p53
C-K320-73-82Q) enhances neurite growth on both permissive and
myelin inhibitory substrates ( Gaub et al., 2010b; Tedeschi, Nguyen,
Puttagunta, et al., 2009 ). Conversely, a p53 mutation that prevents its
acetylation at specific residues in its C-terminus via lysine to arginine
transition (p53 C-K320-73-82R) inhibits physiological neurite outgrowth
in the same primary cerebellar neurons ( Gaub et al., 2010b ). This may be
at least partially due to the fact that p53 acetylated at both Lys 320 and
373 forms a complex with P/CAF and CBP/p300 on the GAP-43
promoter, enhancing its gene expression ( Tedeschi, Nguyen, Puttagunta,
et al., 2009 ). Importantly, p53/CBP/GAP-43 transcriptional module is
also required for facial nerve regeneration following facial nerve axotomy
in vivo ( Tedeschi, Nguyen, Puttagunta, et al., 2009 ). Accordingly, after
sciatic nerve injury in DRG neurons, acetylated p53 at Lys 373 occupy