14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 90

NF-κB and suppress proliferative potential of cells. In breast cancer cells (MCF7,
MDA-MB-231, BT-474, SK-BR-3 and T47D), 14-3-3σ expression was downregu-
lated in comparison with other isoforms. 14-3-3σ is associated with reduced invasion
and metastasis in vivo experimental models. Of interest is that in breast cancer tissues
absence of 14-3-3σ correlated with the presence and activation of NF-κB and mark-
edly reflected in poor prognosis (Ingles-Esteve et al., 2012). These authors suggest a
direct interaction between 14-3-3σ and NF-κB on the basis that three 14-3-3σ bind-
ing sites have been reported in NF-κB protein (Aguilera et al., 2006). Whilst they do
show the effects on the expression of several NF-κB target genes, they have made no
attempt to target their attention on specific genes that regulate the phenotypic effects
of NF-κB (see Table 9.2). Nonetheless, this is a very creditable demonstration of the
inhibitory function of 14-3-3σ. NF-κB is activated by many cytokines and is important
in the production of MMPs. In certain cell lines, for example the lung fibroblast IMR-
90 cell line, MMP-1 is produced in response to 14-3-3β and 14-3-3α but not to 14-3-3σ
(Asdaghi et al., 2012). It seems possible therefore that 14-3-3σ has no effect on cell
migration unlike other 14-3-3 because of its inability to generate MMPs.
Does 14-3-3 σ Influence Wnt Signalling?
The Wnt system is a major developmental signalling pathway whose activation is
an important requisite for many biological phenomena such as stem cell mainte-
nance and maintenance of potential for cell replication. Wnt signalling seems to be
able to interact with NF-κB signalling in the activation of EMT. Hence it is of inter-
est here that attempts have been made to draw together 14-3-3σ with Wnt signal-
ling. However, in somewhat sharp contrast to what one would expect, Chang et al.
(2012a) have attributed the faculty of promotion of cell proliferation of embryonic
stem cells to 14-3-3σ. They have allied together the functions of 14-3-3σ with Wnt
signalling. One would recall the characteristic feature of Wnt signalling is the for-
mation of a multiprotein complex of Axin, GSK-3β, CK1, and APC with β-catenin
when Wnt receptors are not bound by the appropriate ligand. Axin promotes the
phosphorylation of β-catenin with the mediation of GSK-3β leading to the degrada-
tion of β-catenin. The turnover of β-catenin is interceded by β-TrCP (β-transducin
repeat containing protein), which is responsible for its ubiquitination and degrada-
tion. The degradation of β-catenin enables repressor factors to bind to the TCF/Lef
transcription factors to block the transcription of β-catenin responsive genes. In the
presence of the Wnt ligand, the multiprotein complex breaks up and this leads to
the stabilisation and accumulation of β-catenin in the nucleus. The binding of Wnt
ligand to the receptor inhibits GSK-3β and stabilises β-catenin. β-catenin now forms
a complex with the transcription factor TCF/Lef, and the complex is translocated
into the nucleus leading to the transcription of responsive genes (see Figure 6.1).
Chang et al. (2012a) have in fact argued that in embryonic stem cells 14-3-3σ pro-
motes cell proliferation. They have claimed that suppression of 14-3-3σ using siR-
NAs suppressed embryonic stem cell proliferation. This is annulled by β-catenin
knockdown. 14-3-3σ bound and increased GSK-3β phosphorylation and dislocated