14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 86

(IRS) and TGF-β/Smad. EGF/EGFR do stimulate cell migration besides promot-
ing growth. EGFR interacts with 14-3-3σ, possibly this leads to sequestration of
EGFR. Cells transfected with 14-3-3σ showed a reduction in EGFR expression and
cells carrying transfected siRNA against 14-3-3σ showed reduction in the expres-
sion of the latter and enhanced EGFR expression. In vitro , enhanced 14-3-3σ expres-
sion and reduction in EGFR led to reduced cell motility. In the opposite scenario
with reduced 14-3-3σ and attendant increase of EGFR expression cell motility was
enhanced (Huang et al., 2010). These transfectants do not appear to have been tested
in metastasis assays. The presence of 14-3-3σ also inhibits the normal function of the
EGFR family receptor HER2 (erbB2). Ling et al. (2012) have shown recently that
loss of one or both alleles of 14-3-3σ lead to accelerated growth of mammary and
salivary tumours in mice, in the background of activated HER2. They demonstrated
that with the loss of 14-3-3σ MAPK signalling, but not PI3K/Akt, was activated and
compatibly there was an increase in proliferation and no effect on apoptosis was
seen. Finally, Ling et al. (2012) show that loss of 14-3-3σ increases both invasion
and metastatic ability. However, in respect of the last parameter only the lungs of
tumour-bearing animals were checked for metastases. 14-3-3σ expression downregu-
lates HER2. Loss of 14-3-3σ upregulates HER2 as well as the transcription factor
EGR2/CITED1. Indeed EGR2 binds to HER2 and leads to the relocation of the com-
plex to the cytoplasm thus sequestering the regulatory transcription factor (Dillon
et al., 2007).
The inhibitory effect of 14-3-3σ contributes to TGF-β1-mediated growth inhi-
bition. But 14-3-3ζ negatively regulates growth inhibition by TGF-β (Hong et al.,
2010), compatible with their known opposing effects on cell proliferation. However,
one ought to be circumspect about experimental models operating in the backdrop
of TGF-β, for this has a differential function in early transformation and tumorigen-
esis where it exerts an inhibitory effect, whilst promoting invasion and metastases at
later stages of tumour development. Equally, EMT is activated by TGF-β, EGFR and
HER2 receptors.
Regulation of Cell Cycle Checkpoints by 14-3-3 Proteins
The maintenance of genomic integrity requires that cells are prevented from entering
into mitotic or meiotic division when DNA replication is incomplete. DNA replica-
tion checkpoints control cell cycle progression. DNA damage response is regulated
by the ATM protein, a kinase similar in homology to PI3K. ATM is activated by
MRE11 (meiotic recombination 11)/Rad50/NBS1 (Nijmegen Breakage syndrome 1)
complex linked with DSB (double strand break) damage recognition and repair and
checkpoint regulation (Carney et al., 1998) or 53BP1. The latter is involved with
G2-M and S-phase checkpoint regulation (Wang et al., 2002).
Three DNA damage surveillance checkpoints have been identified and defined.
These are the G1-S transition checkpoint, which restrains cells with damaged DNA
from entering the S-phase. The second checkpoint, namely the S-phase check-
point, monitors the progress of cells through the S-phase and regulates the rate of