Biology Reference
In-Depth Information
metabolism, differentiation, and apoptosis in several cells (
Baker et al., 1989;
el-Deiry, Kern, Pietenpol, Kinzler, & Vogelstein, 1992; Lane, 1992;
Murray-Zmijewski, Slee, & Lu, 2008; Riley, Sontag, Chen, & Levine,
2008; Tedeschi & Di Giovanni, 2009
).
p53 activation is classically induced by a number of cellular
stressors including oxidative stress and DNA damage that in turn lead to
p53-dependent cell cycle arrest, DNA repair, or cell death. Activated p53
binds to specific DNA elements on both promoters and intronic regions reg-
ulating the expression of a large number of downstream genes, including
classical gene targets such as the cyclin-dependent kinase inhibitor p21 or
the proapoptotic genes
Apaf-1, Puma, Noxa
, and
Bax
(
Harms, Nozell, &
Chen, 2004
).
p53 activity is fine-tuned and regulated by several posttranslational
modifications (PTMs), including acetylation, phosphorylation,
sumoylation, and neddylation; in fact, specific combinations of PTMs
on p53 amino and carboxyl termini define its promoter specificity and
therefore its function (
Riley et al., 2008
). Furthermore, several proteins
mainly belonging to the proteasome, including the ubiquitin ligases
MDM2, MDM4, COP1, Pirh2, and Mule, tightly regulate p53 transcrip-
tional activity by affecting p53 degradation, stabilization, accumulation,
and subcellular localization (
Coutts, Adams, & La Thangue, 2009;
Coutts, Boulahbel, Graham, & La Thangue, 2007; Lavin & Gueven,
2006
).
In neural biology, p53 plays some typical as well as more unique roles.
In fact, it controls cell cycle progression in neural precursor cells and influ-
ences neuronal cell fate, or in injured neurons, it responds to DNA damage
signals promoting DNA repair and promotes cell death induced by gluta-
mate toxicity or by neurotrophin withdrawal once too high levels of cellular
damage have been reached. However, an increasing amount of literature
indicates that p53 also contributes to some neuron-specific functions being
a key intrinsic regulator of neurogenesis as well as of neurite outgrowth and
axonal regeneration. This is, however, not fully surprising if we consider
that modulation of cell cycle length and exit is crucial for polarity of
self-renewing divisions in neural stem cells as well as for neuronal plasticity,
specification, and differentiation.
Here we review the essential literature supporting a role for p53 in
neuronal development, neurogenesis, and axonal regeneration speculating
on its common function as “intrinsic cellular clock regulator” in these
processes.
