HIC1 Suppressor Gene - Therapeutic Strategies in Cancer Biology and Pathology - page 151

(Chen et al., 2008c). BRCA tumour suppressor proteins interact with several pro-
teins such as BCCIP (a cofactor for BRCA2 in tumour suppression), the DNA repair
proteins Rad50 and Rad51, c-myc, p53 and Rb (Jhanwar-Uniyal, 2003). CtBP and
CtIP (CtBP-interacting protein) also interact with BRCA proteins. The biological
functions of BRCA1 are mediated by two C-terminal BRCT domains. Proteins con-
taining the LIM domain, that is a tandem repeated zinc-finger structure that mediates
interaction between proteins, are known to participate as transcription factors in gene
expression and in many cellular functions such as cell adhesion, motility and sig-
nal transduction. The BRCT domain binds CtIP and interacts with the LIM domain
protein LMO4, thus forming a complex that was suggested to negate the suppressor
function of BRCA1 (Sum et al., 2002). Both CtIP and CtBP suppress the transacti-
vation of the p21 promoter by BRCA1 and again its terminal BRCT appears to be
involved (Li et al., 1999). There is no new information in this regard or in respect of
other tumour suppressors.
Do ARFs Function in Conjunction with 14-3-3 σ ?
The 14-3-3 family of proteins have been studied in some detail on account of the
tumour suppressor function of some members of the family, for example 14-3-3σ.
With the association of p53 with ARF function, the natural follow-up in terms of cell
cycle checkpoint control is to inquire into whether ARF and 14-3-3σ are connected
in terms of their function. The regulation of apoptosis and checkpoint function has
prompted investigation into the relevance of the 14-3-3 proteins in carcinogenesis.
14-3-3σ has been cited as a target for interference to make tumour cells susceptible
to the action of anticancer agents (Hermeking et al., 2003). This may be a theoreti-
cal option, but 14-3-3σ is not known to be expressed to the exclusion of members of
the 14-3-3 family which actively promote cell proliferation and EMT. The induction
of apoptosis by p14ARF via the intrinsic mitochondrial pathway in relation to the
operation and effect of p21 and 14-3-3σ was studied by Hemmati et al. (2008) who
reported that p14ARF induced apoptosis irrespective of the presence or absence of
14-3-3σ. In other words, it would be useful to have an overall picture of 14-3-3 rep-
resentation in the target cells before therapeutic manipulation.
The PARP Pathway
Another important pathway leading to apoptosis is by PARP mediation. This could
conceivably function either dependently or independently of p53. DNA damage
induces PARP activation which then participates in DNA repair. Caspases can break
down PARP, prevent DNA repair and induce apoptosis. On the other hand, there is
a view that hyperactivation of PARP could activate AIF and apoptosis (Yu et al.,
2002), although lately PARP-independent activation of AIF has been advocated
(Kondo et al., 2010).