Biology Reference
In-Depth Information
Sm theta ,2011
). Gp130 is also upregulated by STAT3 activation,
suggesting a positive feedback loop that potentiates STAT3's effects
(
O'Brien & Manolagas, 1997; Smith et al., 2011
). STAT3 activation is also
implicated in epigenetic modulation, raising a possibility that epigenetic
mechanisms contribute to STAT3-mediated axon growth (
Trakhtenberg &
Goldberg, 2012
). STAT3 has been shown to turn on transcription of an
epigenetic regulator DNA methyltransferase 1 (DNMT1) in cancer cell
lines, and in the same context, activated STAT3 forms transcriptionally
repressive complexes with DNMT1 and histone deacetylase 1 at the
promoter of SHP-1 phosphatase, a tumor suppressor. The repression is
mediated in part by promoter silencing through DNA methylation
(
Zhang et al., 2005, 2006
). Moreover, in the epithelial cell line MCF-10,
STAT3 activation is able to upregulate expression of miR-21 which has
been implicated with a pro-regenerative role in adult DRG neurons after
axotomy (
Iliopoulos, Jaeger, Hirsch, Bulyk, & Struhl, 2010; Strickland
et al., 2011; Trakhtenberg & Goldberg, 2012
).
While the STAT3-mediated effect is attributed mainly to its nuclear
transcriptional role, evidence suggests that STAT3 could also act through
nontranscriptional mechanisms. STAT3 interacts with microtubules to pro-
mote cell migration, an effect that is mediated by its competition with the
binding of the microtubule-associated protein stathmin (
Ng et al., 2006
).
STAT3 is also found in mitochondria (
Wegrzyn et al., 2009
). Mitochondrial
STAT3 regulates metabolic function in mitochondria to support growth of
certain types of cancer cells (
Gough et al., 2009
). More recently, mitochon-
drial STAT3 was shown to facilitate neurite outgrowth in response to nerve
growth factor (NGF). NGF increases the level of STAT3 serine but not ty-
rosine phosphorylation in PC12 cells and cortical neurons, and serine phos-
phorylated STAT3 was localized in mitochondria but not in the nucleus.
A serine DN-STAT3 mutant attenuates NGF-stimulated neurite out-
growth, suggesting a role for mitochondria-targeted STAT3 in facilitating
axon growth (
Zhou & Too, 2011
). Recent findings also indicate STAT3
as an injury signal retrogradely conveyed from the site of lesion to the cell
body. After peripheral nerve injury, phosphorylated (i.e., active) STAT3 is
detected in the injured axons and later in the soma (
Lee, Neitzel, Devlin, &
MacLennan, 2004
). A subset of STAT3 transcripts is axonally targeted at the
default state by its 3
0
UTR. Upon axonal injury, the STAT3 protein is locally
synthesized and phosphorylated in axoplasm. This activated form of
phosphorylated (p)-STAT3 is then packaged into the dynein-transport path-
way by interaction with the Importin system and retrogradely transported.
