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(discussed in pp. 3 and 4) and these seem able to promote methylation of CpG sites
(Jones et  al., 1999; Wassenegger, 2000; Suzuki et  al., 2008). The heterochromatic
siRNAs are involved in the maintaining genomic integrity by DNA methylation and
modification of histones (Katiyar-Agarwal et al., 2006; Matzke et al. 2009).
As discussed previously siRNA can be appropriately targeted to inhibit S100A4.
With directed methylation, one can suppress S100A4 expression and in this way
control the aberrant behaviour of cells. This approach could downregulate S100A4
and effectively restore nm23 function (Sherbet, 2009). Indeed this might constitute
a bimodal suppression of tumour invasion and metastasis. There is currently little
activity aimed at testing HDAC inhibitors and DNA methylation for inactivation of
metastasis promoter genes.
Is Tumour Suppressor p53 a Route to nm23 Manipulation?
The suppressor gene p53 is generally accepted as a negative regulator of the cell
cycle. The possibility that p53 might provide a means of manipulating nm23 expres-
sion has been seriously considered. Several attempts were made in early years to
establish a connection between the expression of p53 and nm23. No firm conclu-
sions could be drawn from most the studies due to flawed experimental design and
the lack of understanding for the need to demonstrate simultaneous or co-expression
of these proteins and also from the lack of appreciation that p53 protein was detect-
able by immunohistochemical procedures due to the enhanced half-life of the pro-
tein either by conjugation and stabilisation with other cellular proteins or the protein
occurred in the mutated form. So overall, most of these studies were poorly informa-
tive and inadequate to establish any notion of correlation between the variables.
Sometime ago, Chen et al. (2003a) linked p53 signalling and nm23-H1in MCF-7
and J7B cells with the demonstration that nm23-H1is upregulated by wild-type p53
and paralleled by inhibition of the invasive ability of the cells, but then nm23-H1 is
downregulated by p53 in RKO and H1299 cells together with increase of invasion.
This differential effect seen in different cell lines could be due to the involvement of
other factors associated with p53 signalling. STRAP (serine-threonine kinase recep-
tor-associated protein; stress-responsive activator of p300) is known to be a regulator
of p53 signalling. STRAP is co-ordinately regulated by ATM (ataxia telangiecta-
sia mutated) and Chk2 (Checkpoint kinase 2) kinases upon DNA damage (Adams
et  al., 2008). STRAP seems to be able to promote recruitment of p53-coactivators
and could also antagonise mdm2, which is itself a negative regulator of p53. Now
nm23-H2 can interact with mdm2 (Polanski et  al., 2011). Jung et  al. (2007) have
shown that nm23-H1 and STRAP directly interact with p53 and enhance p53 activ-
ity. Also p53 activation by nm23-H1 and STRAP occurs as a result of the removal of
mdm2 from its complex with p53. A general conclusion would be that the interaction
between nm23 isoforms with p53 signalling might result both in the inhibition of
invasion and activation of the apoptotic pathway. It is worthy of note here that nm23-
H1 has been postulated to possess 3′-5′ exonuclease activity and ascribed a role in
the induction of apoptosis independently of the caspase pathway.
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