Biology Reference
In-Depth Information
Activation of PI3K signalling subserves many cellular functions. An important
downstream effector of PI3K signalling is mTOR, which participates in the regula-
tion of mitogenic signals, among others (Wullschleger et  al., 2006). Akt links and
co-ordinates signals accrued from activated receptors with downstream effectors to
generate phenotypic effects of proliferation and cell motility. Thus the PI3K/Akt/
mTOR pathway is pre-eminently involved in the regulation of cell proliferation,
growth, apoptosis and cell motility. A link with this signalling system is indicated
by the ability of miRNA-21 to regulate the PI3K/Akt/mTOR pathway by operating
via PDCD4. This signalling is in turn subject to the function of the tumour suppres-
sor PTEN, which can negatively regulate PI3K/Akt/mTOR signalling. MiRNA-21 is
able to inhibit apoptosis and it seems to achieve this by regulating the expression of
PTEN (Chan et al., 2005; Meng et al., 2007).
MiRNA-21-mediated inhibition of PDCD4 can occur by other means. Inhibition
of MAPK signalling pathway might be involved here (Yang et al., 2006). From their
study of gastric tumours, Li et  al. (2011c) have provided some indirect evidence
for this. They found miRNA-223 is able to downregulate EPB41L3 expression by
directly targeting its 3′-untranslated regions. As further subsidiary evidence they
state that overexpression of miRNA-223 in primary gastric carcinomas correlated
with poor metastasis-free survival.
In this context, one should cite the recent findings of Imanaka et al. (2011). They
found miRNA-141 to be highly expressed in cisplatin-resistant cells, and further that
enforced expression of miRNA-141 in cisplatin-sensitive cells increased cell viabil-
ity. They found that this miRNA-141 targeted and downregulated YAP1 expression.
One would recall that YAP1 (the 65 kDa YAP transcriptional co-activator, see also
Hippo signalling pathway, pp. 155-160) is an important mediator of p73-mediated
apoptosis. YAP1 binds to p73, regulates its transcriptional activity and p73-depend-
ent apoptosis. Akt phosphorylates YAP to inhibit its binding to p73. YAP is said to
be able to stabilise p73 in response to DNA damage and induce p73-dependent apop-
tosis. By virtue of its ability to induce apoptotic cell loss, YAP has been labelled as
a tumour suppressor (Di Agostino et  al., 2010). This pathway can conceivably also
link up with PTEN/Akt signalling in apoptosis.
The PI3K/Akt/mTOR and MAPK/ERK pathways have been suggested to be
involved in another putative function of PDCD4. Suppression of the latter using shR-
NAs has been shown to increase angiopoietin-2 (Ang-2) mRNA and protein (Krug
et al., 2012). These authors have argued without much conviction that PI3K/Akt route
rather than MAPK/ERK might be operating in their experimental setup. Surprisingly
the bHLH transcription factor HIF-1 and its transcriptional target VEGF were not
affected in any way. Indeed signalling via both PI3K/Akt/mTOR and MAPK/ERK
pathways might operate in the induction of angiogenesis.
Can PDCD4 Be Manipulated for Therapy?
The loss of PDCD4 in human tumours with attendant effects on tumour growth,
invasion and progression inevitably raises the question whether PDCD4 loss can
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