14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 87

DNA repair DNA damage DNA repair

BRCA MRE

AT M -P

c-Abl

p53 p53

SAPK p73 Chk2 Chk1

BRCA1

Cdc25 Cdk1

P21 / 14-3-3

Cdc2 14-3-3 Cdc5

Checkpoint Checkpoint

arrest arrest

G2-M

progression

Survival apoptosis Apoptosis

Figure 14.2 Pathways of ATM-mediated checkpoint regulation, apoptosis and cell survival.
14-3-3 might participate in G2-M arrest by the p53/21 and also Cdc25/Cdc2 axes of
signalling. Cdc25 dephosphorylates and activates Cdc2 kinase. ATM signalling via NF-κB
is not shown here.

DNA synthesis. The third checkpoint monitors the G2-M boundary. DNA damage
response involves many signalling pathways that regulate cell cycle checkpoints,
DNA repair and apoptosis programmes; these help to maintain genomic integ-
rity. The checkpoint kinases Chk1 and Chk2 function downstream in DNA damage
response. They are important participants in the network that maintains genomic
integrity. Chk2 has an essential role in p53-dependent apoptosis. Indeed, checkpoint
kinases have been regarded as tumour suppressor genes. These modes of genetic
defence would be counterproductive to cancer management by chemo- and radio-
therapy (Sherbet, 2003, 2011a). The ATM pathway involves the downstream check-
point kinases Chk1 and Chk2, the suppressor proteins p53 and BRCA1 as well as
c-Abl and NF-κB. The checkpoint kinases in turn target Cdc25/Cdc2. Thus emerges
a composite picture in which ATM regulates many signalling systems that culminate
in DNA repair, apoptosis or cell survival ( Figure 14.2 ).
With this prelude a discussion of the role of 14-3-3 proteins in the repair of
DNA damage and the regulation of cell cycle checkpoints seems highly appropri-
ate. Indeed, the diversity of pathways that engage these proteins would make this
an imperative from the point of view of therapeutic approaches with 14-3-3 because
the checkpoint kinases have also been regarded as potential tumour suppressors.
The fission yeast proteins Rad24 and Rad25 have been identified as homologous
with mammalian 14-3-3 proteins (Ford et al., 1994). As stated earlier, Chk1 targets
and phosphorylates Cdc25 and in this process creates a Rad24/25 (14-3-3) binding