Biology Reference
In-Depth Information
16
The ING (Inhibitor of Growth)
Suppressor Gene
The ING (inhibitor of growth) gene, which exerts wide-ranging biological effects
on cell proliferation, regulation of the cell cycle, apoptosis, ageing, DNA repair and
tumorigenesis. Its products are putatively thought to be tumour suppressors by virtue
of their ability to modify chromatin structure and regulate genetic transcription. ING
proteins contain the PHD plant homeodomain, a highly conserved zinc finger motif
implicated in chromatin mediated regulation of genetic transcription, in the C-terminal
end. ING proteins have N-terminal sequences required in their interaction with HAT
and HDAC which enables them to regulate promoter activity of target genes. ING is
downregulated in many tumours. Reduced expression may occur together with genetic
changes that might compound the inhibitory functions of ING proteins.
ING3 downregulation has been reported in HCC tissues and this correlated with
tumour grade with inhibited expression being associated with Edmondson-Steiner
grade II-III tumours (Lu et al., 2012). In head and neck squamous cell carcinomas,
there is a differential relationship between intracellular location of ING and tumour
grade. Nuclear expression of ING4 decreased from normal epithelium to dysplasia and
on to carcinoma and with TNM stages. ING4 levels in the nucleus also positively cor-
related with apoptosis. But cytoplasmic levels positively correlated with lymph node
metastasis and consistent with this also correlated with 14-3-3η, a tumour promoter
(Li et al., 2011d). This appears to be a consequence of ING4 binding to the 14-3-3 and
being localised in the cytoplasm and prevented from performing its function. Such a
functional inactivation by being restricted to the cytoplasm has been shown to occur,
for example, in the case of ING1b (Gong et al., 2006). However, Li et al. (2011d) only
demonstrated the co-expression of 4-3-3η and ING4 in the cytoplasm, not their bind-
ing to each other. Nevertheless, reduced nuclear levels of ING4 were correlated with
the tumour stage and lymph node metastasis. ING4 expression was lower in grade III
than in grade I-II tumours. In lung cancer, reduced ING4 mRNA has correlated with
tumour stage and lymph node metastasis (Jara-Lazaro et al., 2010).
Adenovirus mediated transfer of ING4 brings about a host of alterations in
recipient MDA-MB-231 breast cancer cells, among them induction of G2-M arrest
and apoptosis together with upregulation of P21, P27 and Bax, and downregula-
tion of Bcl-2, IL-8. Intratumoral introduction of ING4 into tumours formed by
MDA-MB-231 cells in nude mice led to growth inhibition (Li et al., 2010i). MCF-7
cells overexpressing ING4 by gene transfer showed suppression of cell proliferation
and cessation of the cell cycle at G0/G1 and enhanced apoptosis. There was enhanced
expression of p21 and Bax mRNA (Wei et al., 2012b). Mutations of ING4 have been
recorded and these inactivated the suppressor protein and reduced its ability to inhibit
proliferation, cell migration and to induce apoptosis (Moreno et al., 2010).
Search WWH ::
Custom Search