14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 84

↑14-3-3 σ

BRCA/p53

P21/p27

RTKs PI3K/Akt NF - κ B RASSF

Checkpoint
arrest

Cell proliferation/apoptosis

Figure 14.1 The postulated 14-3-3σ suppressor signalling pathways. Other isoforms of
14-3-3 which promote cell proliferation and inhibit apoptosis also by regulating the signals
in the opposite direction to that of 14-3-3σ. 14-3-3σ signalling might also engage mTOR,
Wnt and Hh pathways. The isoforms that can stimulate cell motility have been suggested to
function via the MMP system.

P53 in 14-3-3 Function

The generally postulated suppressor function of 14-3-3σ would only be compatible
if it were shown to inhibit cell proliferation and this would not be consistent with
self-renewal capabilities of stem cells, whether of embryonic or adult origin. Indeed,
contrary to conventional thinking embryonic stem cell survival and maintenance may
be an important area in developmental and cancer stem cell biology, where 14-3-3s
might play a role. The whole array of 14-3-3 isoforms has been detected in embry-
onic stem cells. Inhibition of 14-3-3σ with siRNA reduces stem cell proliferation.
Furthermore 14-3-3σ has also been found to interact with Wnt signalling (Chang
et al., 2012a), which as noted elsewhere collaborates with Hh signalling.
In a series of breast cancers not only was 14-3-3σ expression reduced but this
correlated with that of p73 (Geng et al., 2011), which ties in with both p53 and p73
directly targeting 14-3-3σ with a pro-apoptotic outcome. Indeed p53 protein binds
to certain consensus binding sequences that have been identified in the promoter of
14-3-3γ which is not only highly expressed in lung tumours but high expression
correlates with p53 mutations with the implication that wild-type p53 might regulate
14-3-3γ expression (Radhakrishnan et al., 2011b). Wild-type p53 bound to the con-
sensus sequence. However, when this motif was deleted, the ability of p53 to sup-
press 14-3-3γ expression also disappeared. This provides a conceptual nexus between
14-3-3 proteins and p53 family proteins with cell proliferation, but the caveat remains
that loss of function mutation of p53 would influence proliferation status without ref-
erence to 14-3-3γ expression. Nonetheless, a causal link does exist between expres-
sions of 14-3-3σ and p53. 14-3-3σ is a p53 inducible protein and may regulate p53,
and stabilise its expression by suppressing its ubiquitination. It has also been shown
to promote p53 oligomerisation and increase its transcription activity (Yang, 2003b).
Su et al. (2011) has been shown most persuasively that DNA damage results in the
diminution of COP1 (constitutive photomorphogenic 1), an E3 ubiquitin ligase. COP1
is a repressor of photomorphogenesis in plants which targets p53 for proteasomal deg-
radation via ubiquitination (Dorman et al., 2004). The reduction of COP1 would be
expected to result in the prevention of ubiquitination of p53 and lead to its stabili-
sation. In contrast in 14-3-3σ (−/−) cells, COP1 was not downregulated so allowing