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and wiring in postmitotic neurons. The RhoGTPase family of proteins is
critical for the modulation of neurons motility by regulating actin dynamics;
in fact, suppression of Rho kinase (ROCK) activity by using a ROCK
inhibitor is needed to rescue growth cone collapse induced by inhibition
of p53 phosphorylation (
Qin et al., 2009
). Specifically, functionally active
phosphorylated p53, localized directly at the growth cone during neurite
outgrowth in hippocampal neurons, inhibits local ROCK activity at the
growth cone and protects from collapse (
Qin et al., 2009
). Furthermore,
local axonal downregulation of p53 expression levels has also been associated
with axonal impairment during postnatal development in a mouse model of
Niemann-Pick type C syndrome (NPC), a neurodegenerative lysosomal
storage disease (
Qin, Liao, Baudry, & Bi, 2010
). In agreement with these
findings, treatment of NPC-affected mice with a ROCK inhibitor leads
to rescue in p53 expression levels and to a subsequent improvement in
axonal development and outgrowth (
Qin et al., 2009
). Interestingly, the
truncation of phosphorylated p53 by calpain activity, associated with
semaphorin 3A-induced growth cone collapse, results in cytoskeleton reor-
ganization by activating ROCK (
Qin et al., 2009
). Semaphorin 3A-induced
calpain activation depends on the activation of ERK and p38 MAPK, which
may phosphorylate p53. Finally, p53 has also been described as a transcrip-
tional inducer of the ROCK-dependent actin-binding kinase LIMK2 (
Croft
et al., 2011
), further suggesting a link between p53 activity and cytoskeleton
remodeling.
Usually, transcription factors do not act alone; rather they cooperate and
interact with cofactors to form transcriptional complexes competing for pro-
moter occupancy.
There are several other transcription factors that have been shown to be
crucial for the intrinsic regulation of axonal regeneration and at the same
time to intersect with p53-dependent signaling (
Di Giovanni & Rathore,
2012
), but so far, their interplay has rarely been considered in the context
of neurite outgrowth and axonal regeneration.
The classical p53 transcriptional cofactors and acetyltransferases CBP/
p300 and PCAF have been shown to be required and to enhance p53-
dependent promoter occupancy and gene expression of Coronin 1b, Rab
13, and GAP-43 during neurite outgrowth in both PC12 cells and primary
neurons (
Di Giovanni et al., 2006; Gaub et al., 2010b; Tedeschi, Nguyen,
Puttagunta, et al., 2009
). CBP/p300 and PCAF are also capable of
enhancing p53-dependent effects upon neurite outgrowth in primary
neurons (
Gaub et al., 2010a
). This is likely due to both p53 and histone
