Biology Reference
In-Depth Information
Another p53-related tumor suppressor gene involved in the regulation of
neural stem cells proliferation and self-renewal is PTEN. Both embryonic and
adult neural stem lacking PTEN show increase in proliferation; however, in
contrast with p21 deletion, they retain their neurogenic potential and they do
not show signs of exhaustion (
Gregorian et al., 2009; Groszer et al., 2006
).
PTEN-null mice exhibit an increased olfactory bulb mass, and following
focal stroke, PTEN deletion enhances the number progenitor cells that
proliferate and migrate toward the lesion site (
Gregorian et al., 2009
).
Microarray analysis revealed that loss of PTEN enhances G
0
-G
1
cell cycle
exit by dysregulating cell cycle-related genes (
Groszer et al., 2006
).
Overall, PTEN loss promotes self-renewal of neural progenitor/stem cells
by disruption of the homeostatic mechanism that controls their proliferation.
Potentially, the same mechanism could also be implicated in brain
tumorigenesis; indeed, losses of function mutations in PTEN are known
to be involved in the genesis of glial tumors. A subset of cancer stem cells
that might originate from neural stem cells in the adult subventricular zone
contribute to the formation of glioblastoma, the most lethal of all glial
tumors. Because p53 controls PTEN transcription and
TP53
mutations
are well involved in glioblastoma formation (
Zheng et al., 2008
), it is tempt-
ing to speculate that dysregulation in neural stem/progenitor cells cycle and
increase in their exit from G
0
to G
1
might be crucial in promoting glioblas-
toma formation. In fact, changes in stem cell polarity between symmetric
and asymmetric division have been suggested as a mechanism involved in
tumorigenesis, and p53 loss of function switches the polarity of cell division
in mammary stem cells in favor of symmetric division, leading to tissue over-
growth and increasing the tumorigenic potential (
Cicalese et al., 2009
).
Together, these findings suggest p53 as a major gatekeeper against disruption
of polarity of self-renewing divisions in neural stem cells during both
embryonic development and adulthood.
3. p53 IN NEURITE GROWTH AND AXONAL
REGENERATION
Cessation of proliferation and exit from the cell cycle is directly linked
to neuronal differentiation; however, the mechanisms that regulate the
transition between these two stages remain still elusive. Besides its
well-described proapoptotic effect, a novel role for p53 in regulating neu-
ronal differentiation, neurite outgrowth, and axonal regeneration is cur-
rently emerging. The first hint pointing to an important role for p53 in
