14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 89

is also an interacting partner of 14-3-3 proteins in the yeast and in mammalian cells.
Deficiency of the protein leads to lack of hyperphosphorylation of Exo1 and persis-
tent stalling at the replication fork leaves lesions of DNA damage as single strand
gaps as seen by EM. Exo1 is phosphorylated at three Ser/Thr motifs and is a poten-
tial target of 14-3-3 proteins. Interaction between the latter and Exo1 occurs in vitro
(Andersen et al., 2012). Thus 14-3-3 proteins may modulate Exo1 phosphorylation
status and possibly affect DNA repair and cell cycle progression. It would not be
out of place to mention here that in the fission yeast Schizosaccharomyces pombe
Dss1p DNA recombination repair protein has been found to recruit Rad24, which is
a 14-3-3 homologous protein, to DSBs (Selvanathan et al., 2010). Rad24 probably
also takes part in cytokinesis (Mishra et al., 2005).
Response of cells to DNA damage involves induction of G1 arrest by p53-mediated
transcription of target genes such as p21 waf1 and the inhibition of cdk activity. 14-3-3σ
is upregulated by the suppressor genes p53 and BRCA1, which are both closely allied
to the upregulation of cdk inhibitors p21 waf1 and p27 kip1 leading to the inhibition of cell
proliferation and tumour suppression. The expression of p73, another member of the
p53 family, also correlates positively with 14-3-3σ. Overexpression of the latter upreg-
ulates p73 and inhibits tumorigenicity (Geng et al., 2011). Compatible with this, the
expression of 14-3-3σ has been associated with drug resistance in breast cancers (Liu,
2006). 14-3-3σ might collude with p53 in the development of drug resistance. For, as
noted earlier not only is 14-3-3σ a p53 inducible protein but it may also regulate p53,
stabilise its expression by suppressing its ubiquitination. 14-3-3σ has also been shown
to promote p53 oligomerisation and increase its transcription activity (Yang, 2003b)
to occur quite independently of wild-type or mutated p53. However, mutation of p53
does contribute to drug resistance instigated by 14-3-3σ. A specific p53 mutation has
been claimed to confer multi-drug resistance on cells and this effect seems to be a
result of transactivation of the mdr-1 gene and increase of P-glycoprotein levels (Chan
and Lung, 2004). Although these findings suggest a direct link of 14-3-3σ with DNA
repair, one cannot exclude other means of activating p21 waf1 transcription. The tumour
promoter MTA (see pp. 77-79) is capable of repressing the transcription of p21 waf1
independently of p53 (Li et al., 2010b). On the other hand, 14-3-3σ is said to stabilise
p53 and enhance the sensitivity of 5-FU-resistant MCF7 cells to 5-FU, mitoxantrone
and cisplatin. The stabilisation of p53 would effectively inhibit Akt and downstream
of survivin, Bcl-2, NF-κB and NF-κB1 (p50) (also see below) reducing cell survival
and aiding the cytotoxic effects of 5-FU (Zheng et al., 2012). Besides, p73 can activate
the transcription of genes that are targeted by p53 and acts quite independently of p53
(Zawacka-Pankau et al., 2010).
14-3-3 σ and NF- κ B Survival Pathway
NF-κB are a family of transcription factors that activate many genes that are closely
concerned with inflammation, cell survival, cell proliferation and apoptosis, angio-
genesis, cell adhesion, invasion and metastasis (see Table 9.2). The NF-κB survival
pathway has been invoked in the suppressor function of 14-3-3σ. The latter can inhibit