Inhibitor of DNA Binding Proteins in Tumours - Therapeutic Strategies in Cancer Biology and Pathology - page 183

and stabilises IDs, so promoting cell proliferation. When USP1 is suppressed, IDs
are ubiquitinated and destabilised leading to cell cycle arrest and apoptosis (Cotto-
Rios et al., 2011). Ubiquitin/proteasome-mediated degradation of ID1 seems to lead
to TNF-α-induced apoptosis in prostate cancer cells (Ling et al., 2006). But equally
this can occur by other routes, for example by ubiquitination of NF-κB which TNF-α
is known to activate. USP11 can negatively regulate TNF-α-induced activation of
NF-κB (Sun et al., 2010). The Pax transcription factors are differentiation markers
and are arguably valid for CSC markers. Pax7 has been shown to induce ID2 and
ID3 and block premature differentiation of quiescent satellite myogenic stem cells
(Kumar et al., 2009).
Some evidence has emerged relating to ID4. The latter has also been attributed
with gliomas stem cell promotion by enhancing Sox2 expression but by an indirect
route, namely by negating the suppressor effects of miRNA-9*, the 3′ transcript of
miRNA-9 (Jeon et al., 2011). Earlier Jeon et al. (2008) had shown that ID4 might
be functioning via cyclin E and notch signalling. Whilst cell proliferation is an inte-
gral part of CSC propagation, one ought to make a distinction between purely pro-
liferating subpopulations and CSCs. Cell proliferation is not obligatory in CSCs
and markers such as Nestin may be expressed with no proliferation marker (Ernst
and Christie, 2006). The difficulties arise with markers for proliferation signalling
employed with or without standard CSC markers.
Dependent upon the biological model, various markers such as Wnt proteins,
SFRP, the negative regulators of Wnt, and the transcription factors Oct have been
employed as haematopoietic CSC makers, and Pax and Sox transcription factors as
differentiation markers. In the absence of standard protocols, it is difficult to assert
the intrinsic ability of the IDs in the promotion and maintenance of CSCs or the pro-
motion of their differentiation.
One should also bear in mind the potential effects of other suppressor genes on
the CSC markers. LKB1 regulates many of the markers, such as Oct, Sox 2 and
Nestin. Oct4 and Sox2 tend to be overexpressed in the absence of LKB1 expression,
together with suppression of differentiation markers such as Nestin.
Do ID Proteins Activate Other Signalling Systems and
Promote Cell Proliferation?
In common with other bHLH proteins, one can expect that they would be involved
in activation of some and repression of other genes. Therefore hardly surprising it is
that ID4 with notable exceptions functions as a suppressor of tumour growth, inva-
sion and metastasis. Also subject to confirmation (see below), forced expression
of ID1 promotes apoptosis and reduces cell proliferation provisionally attributed
to S-phase arrest and a prolonged G2-M. Attendant upon these are changes in the
expression of cell cycle regulatory p53 pathway, enhancing the expression p21, p27
and their regulator p53 (Carey et al., 2009). Given that loss of p21 and p27 might
lead to tumour progression, the effects on these proteins by ID4 are compatible