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further demonstrates the growth-promoting effect of STAT3 in CNS re-
generation. By combining in vivo imaging with genetic manipulations in
mice, Bareyre and colleagues showed that overexpression of wild type or
constitutively active form of STAT3 substantially promoted axon regen-
eration even after a CNS lesion. Upon activation, STAT3 also induces
the upregulation of its endogenous inhibitor, suppressor of cytokine
signaling 3 (SOCS3), preventing the STAT3-mediated signaling from
over-activation ( Levy & Darnell, 2002 ). Notably, removal of SOCS3-
mediated suppression of STAT3 by conditional knockout of SOCS3
can lead to significantly improved optic nerve regeneration. The en-
hancement of regeneration in SOCS3 mutant axons requires gp130, as
no regeneration was detected upon double-deletion of SOCS3 and
gp130 ( Smith et al., 2009 ). Interestingly, STAT3 has been shown to
be phosphorylated by Cdk5 at Ser727 in vivo , since Ser727 phosphoryla-
tion of STAT3 was essentially absent from cdk5 / brains ( Fu et al.,
2004 ). Further experiments show that Cdk5-dependent phosphorylation
of STAT3 enhances its DNA-binding ability and transcription activities.
Conversely, suppression of Cdk5 activity by its pharmacological inhibitor
roscovitine attenuates the induction of target gene expression triggered
by neuregulin in myotubes ( Fu et al., 2004 ). Remarkably, under regen-
erative condition, Ser727 phosphorylation of STAT3 has been observed
to be induced after spinal cord injury ( Tsai et al., 2007 ). Given that
Cdk5-dependent phosphorylation is important for maximal activation
of STAT3, it is tempting to speculate that Cdk5 may also regulate axon
regeneration through modulating STAT3 activity.
Aside from STAT3, another transcriptional factor implicated in axon
growth and regeneration, p53 has also been identified as a substrate of
Cdk5. In developing neurons, p53 is crucial for neurite growth, as inhibition
of p53 activity results in decreased neurite length. Aside from its role in nor-
mal neurite growth, p53 is also necessary for axon regeneration, as p53 /
mice exhibited a marked reduction in the number of regenerating fibers after
peripheral lesion ( Di Giovanni et al., 2006 ). Notably, phosphorylation
of p53 at multiple sites by Cdk5 stabilizes and activates p53, which in turn
contributes to the expression of its target genes in the paradigm of stress-
induced neuronal cell death ( Lee, Kim, Lee, & Kim, 2007 ). Since p53 is
stabilized and activated by Cdk5, it will be interesting to further examine
whether Cdk5-mediated phosphorylation of p53 also contributes to the
induction of regeneration-promoting genes.
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