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assemble at regions of ID4 promoter and transcriptionally enhances its expression,
ID4 now stabilises certain pro-angiogenic factors thus bringing together mutant p53
function and induction of angiogenesis (Fontemaggi et al., 2009). Given that IDs
can act as inducers of angiogenesis, this study provides a tangible link between ID4
function in conjunction with mutated p53. There are suggestions that IDs might link
up with Rb protein, another cell cycle regulator.
IDs being small proteins would be able to freely translocate between the cyto-
plasmic and nuclear compartment. Nonetheless, how their subcellular distribution
is altered in response to growth factors and other signalling modulators is not fully
understood. It is needless to emphasise here that reconciliation is required of this
angiogenesis promoting ability with the tumour suppressor capability attributed to
ID4. ID4 is known to form complexes with and sequester other bHLH transcription
factors in the cytoplasm and prevent their biological function. Induction of overex-
pression of cytoplasmic ID4 by BMP promotes the translocation of the transcription
factors OLIG1 and OLIG2 and they are sequestered by ID4 (Samanta and Kessler,
2004). Many genetic programmes are activated in a temporal sequence during
tumour development and progression. It may be that IDs display a stage-dependent
and differential subcellular distribution that could account for the tumour suppressor
function of ID4 early in the development of a tumour and induction of angiogenesis
occurring as subsequent event and also explain the tumour and proliferation promot-
ing abilities of the other IDs. This is in the realm of speculation, but it needs to be
explored in the light of IDs participating in stem cell propagation and maintenance
as discussed below.
IDs in Cancer Stem Cell Propagation and Maintenance
An important question being asked is whether IDs participate in stem cell perpetu-
ation and maintenance or induction of their differentiation. The answer when a
definitive one is available is of immense therapeutic value. ID2 and ID4 have been
connected with the differentiation of CSCs. In glioblastoma, cultures containing
CSCs have shown overexpression of ID2 and ID4. Wu et al. (2012c) have explored
a possible link between these. Induced overexpression of the IDs seemed to promote
differentiation of the CSCs as indicted by reduced expression of CSC markers.
Contrary to this, ID1, ID2 and ID3 have been found to enhance neural stem
cell proliferation and maintenance. Nestin and the transcription factor Sox2 com-
monly linked with proliferating neural stem cell were employed as neural stem cell
markers. Forced expression of the IDs generated more Ki-67+ and Sox2 express-
ing cells (Jung et al., 2010). Williams et al. (2011) found that deubiquitination of
ID proteins promoted their stability and stem cell features in osteosarcoma. In some
human osteosarcomas USP (ubiquitin-specific peptidase), a deubiquitinating enzyme
and IDs displayed parallel upregulation. Experimental suppression of USP1 led to
destabilisation of ID proteins and induced cell cycle arrest. The opposite effects
were observed with forced expression of USP1. The reason for this is that USP1 is
phosphorylated by Cdks and thus prevented from degradation; USP1 deubiquitintes
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