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which is also involved in the early steps of miRNA biogenesis. As noted earlier, the
primary miRNA transcripts are processed by a complex called the microproces-
sor complex formed of an RNase III Drosha (the catalytic subunit) and the protein
DGCR8 (the Pasha protein of Drosophila, the subunit that recognises the substrate)
into pre-miRNAs, then processed into the substantive miRNAs. ING1 is able to bind
to the DGCR8 promoter and controls its transcription through chromatin regula-
tion. ING1 quite clearly affects DGCR8 expression. Induction of ING1 suppresses
cell proliferation and suppression of DGCR8 also was anti-proliferative, which could
suggest that effects of cell proliferation might have occurred via interference with
miRNA biogenesis (Gomez-Cabello et al., 2010). Although these effects do occur
in parallel, the data do not constitute evidence for the direct involvement of miR-
NAs. It is needless to say that a number of miRNAs are upregulated in ING-deficient
cells. High levels of expression of miRNA-192 and also of certain other miRNAs
have been noticed. Gomez-Cabello et al. (2010) found no evidence of p53 binding
to the DGCR8 promoter. Nevertheless, miRNA-192 is p53-inducible (Georges et al.,
2008). MiRNA-192 and others such as miRNA-194 can be transcriptionally acti-
vated by p53; these then modulate mdm2 itself a regulator of p53 (Pichiorri et al.,
2010). So the possibility remains that ING effects can occur by p53 mediation. In
this setting, also to be reckoned with is the cell cycle regulatory Rb protein, which is
targeted and downregulated by miRNA-192 (Feng et al., 2011c). Also relevant here
would be to note that ING members can and do interact with p53. ING4 was shown
to induce G2-M arrest by increasing p21
waf
expression in a p53-dependent man-
ner. Furthermore, the NLS (nuclear localisation signal) domain was suggested to be
involved in the interaction of ING4 with p53, which was disrupted by mutations in
NLS, and this led to disruption of p53 function (Zhang et al., 2004, 2005). Zhu et al.
(2009) found that ING1 variants, for example ING1b and ING1c, altered p53 func-
tion and also induced apoptosis and cell cycle arrest at G0/G1 phase, ING1c upregu-
lated the expression of p53 and also p21
waf1
. The overall effect on cell proliferation
seems to have been compounded by enhanced expression of Bax and downregu-
lation of Bcl-2 expression. They do not rule out possibility that alterations in p53
expression could have arisen from changes in p53 stability. Equally however ING1b
has been described as being able to act independently of p53 (Coles et al., 2008).
They noted that whilst ING1b is capable of inhibiting cell proliferation, this effect
can be enhanced by the absence of p53. The NF-κB survival pathway has also been
implicated in the functioning of ING4. Klironomos et al. (2010) found that ING4 is
downregulated in association with grade in astrocytomas. They also noticed that the
expression of p65 (RelA) subunit of NF-κB was higher in grade IV astrocytomas
than in grade I/II tumours.
To conclude there are several important considerations if ING proteins do arrive
at the stage of clinical deployment. Least among them is that at least one isoform
might support progression. The study of signalling systems that INGs activate is at
a rudimentary stage. So exploration of uses in the clinical setting needs considerable
work on the basics and any thoughts of beneficial deployment are in reality a long
way away.
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