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Nucleotide polymorphisms have been identified in RASSF1A and it is possible
that besides epigenetic silencing, aberrant RASSF functions could arise from these
genetic changes (Gordon et al., 2012). Earlier El-Kalla et al. (2010) reported that
nuclear polymorphism of RASSF1A affected its association with microtubules and
its suppressor function.
RASSFs Regulate Cell Proliferation and Apoptosis
RASSFs induce the auto-phosphorylation and activation of the pro-apoptosis Hippo
kinases, MST1 and MST2. This generalisation may have to be revised with the impli-
cation of other signalling pathways in the regulation of the apoptotic process. RASSFs
might under certain conditions inhibit Hippo signalling and apoptosis. For instance,
Ikeda et al. (2009) found that RASSF6 binds and inhibits MST2 activity and apop-
tosis, but induced apoptosis when released from binding to MST2 by WW45. Thus
RASSF6 seems to possess a direct mode of action independent of Hippo. But then the
pro-apoptotic effect of MST2 may be inhibited by other interactions, for example with
Raf1. RASSF1A is said to break up this complex leading to downstream signalling via
Lats and YAP (Matallanas et al., 2007). Besides, they also seem to promote induction
of apoptosis by TNF and related peptides, possibly also involving MST1 function as
demonstrated in the case of RASSF5 (Park et al., 2010). Induction of apoptosis can
occur by other routes, for example via upregulation of p38 MAPK and inhibition of
Akt mediation quite independently of Hippo (Yi et al., 2011). Activation of Bax and
induction of apoptosis with or without the mediation of caspases is also a possibility
(Ikeda et al., 2007). However, the isoform RASSF1C is said to bring about results that
are not compatible with suppressor function (Reeves et al., 2010). It may be that MST2
might be involved in experimental setup in a manner described by Ikeda et al. (2009).
On the other hand, this might be the beginning of the emergence of differential func-
tioning of the RASSFs and its isoforms. This might not be a purely theoretical exercise
for Reeves et al. (2010) have also gone on to show that RASSF1C not only downregu-
lates caspase expression but also makes tumour cells less sensitive to apoptosis.
RASSF1A might function in collaboration with p53 in regulating apoptosis and
tumorigenesis (Tommasi et al., 2011). This is eminently worthy of exploration in
human malignancies in the light of the fact that p53 is the most frequently mutated
tumour suppressor, especially whether deregulation of p53 function can be countered
and neutralised by RASSF signalling. Equally RASSF1A can inhibit cell prolifera-
tion by upregulating cyclin-dependent kinase inhibitor p21
waf1/cip1
via MAPK/Akt
route and quite independently of p53 (Thaler et al., 2009).
The N-terminal RASSFs May Be Tumour Promoters
Unlike the C-terminal RASFs, the N-terminal RASSFs are probably not tumour sup-
pressors. RASSF7 is not methylated nor mutated in several tumour cell lines studied,
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