Biology Reference
In-Depth Information
acetylation that together potentiate p53 activity and facilitate gene
transcription and expression.
Two transcription factors, KLF4 and STAT3, seem of particular interest
for their cross talk with p53 in neuronal outgrowth and axonal regeneration.
It has recently been shown that conditional deletion of KLF4 in retinal gan-
glion cells (RGCs) enhances axonal regeneration following optic nerve
crush (
Moore et al., 2009
). In fact, KLF4 absence in RCGs is associated with
increase in the expression of regeneration-associated genes. KLF4 mediates
p53-p21 response to DNA damage (
Yoon, Chen, & Yang, 2003; Zhang
et al., 2000
) and is able to directly repress p53 expression binding to its
promoter in cell lines (
Rowland, Bernards, & Peeper, 2005
). The direct
transcriptional regulation that KLF4 exerts on p53 is peculiar and
interesting since most of the p53 regulators act by enhancing the rate of
proteosomal degradation rather than acting on its promoter. This also
suggests p53 as a possible target candidate for the pro-regenerative effect
mediated by KLF4 deletion.
The most relevant regulators of STAT3 signaling are NGF and several
neuropoietic cytokines, including IL6, CNTF, and LIF (
Dziennis &
Alkayed, 2008
). Deletion of both LIF and IL6 leads to impaired axonal
regeneration, reducing the levels of active STAT3 (
Cafferty et al., 2004,
2001
). After peripheral nerve injury, STAT3 translocates into the nucleus
and activates the transcription of regeneration-associated genes including
GAP-43 (
Qiu, Cafferty, McMahon, & Thompson, 2005; Schwaiger
et al., 2000
). Interestingly, p53 and STAT3 compete for acetylation
mediated by CBP/p300 and along the same lines p53 overexpression
decreases STAT3 activation in cell lines (
Lin, Tang, Jin, Jia, & Hsieh,
2002; Paulson et al., 1999; Wang, Cherukuri, & Luo, 2005
).
All together these findings suggest that p53 and STAT3 might be
involved in the same pro-growth transcriptional program modulating and
competing for binding with cofactors and pro-growth signals. Therefore,
it is tempting to speculate that an increase in the availability of such mole-
cules might prompt a pro-growth synergistic effect between STAT3
and p53.
Most of the data regarding p53 signaling in neuronal outgrowth come
from studies in neuronal-like cells or in primary neurons. However, recent
in vivo
experimental evidence has also proposed a primary role for p53 in the
control of axonal regeneration after nerve injury. In fact, p53 is required for
axonal regeneration after facial nerve axotomy as shown by an approxi-
mately 30% reduction in the number of regenerating facial motor neurons
