HIC1 Suppressor Gene - Therapeutic Strategies in Cancer Biology and Pathology - page 149

TNF FasL DNA damage

TNFR CD95 Stress factors p53

Bcl-2 family

TRAF2 TRADD FADD ARF PARP / Damage

Repair genes

Caspases

NF- B JNK PARP ARF

Broken down

Survival

Apoptosis

Figure 26.1 A resumé of apoptosis pathways which involve HIC1. The points of involvement
of HIC1 or CtBP are not shown here but discussed in the text. ARF locus gene products,
cyclin-dependent kinase inhibitors, are closely linked with cell cycle regulation, cell
senescence and apoptosis and differentiation. This is the rationale for including them as a part
of the discussion of apoptosis signalling.

encodes thee p14ARF (homologue of murine p19ARF). These genes encode cyclin-
dependent kinase inhibitors. They are involved with both p53 and Rb signalling path-
way. Phosphorylation of Rb by cdk4/6 is regulated by p16ARF, and p19ARF has
been implicated in the regulation of mdm2 and p53 degradation (Li et al., 2009c;
Serrano, 2000; Sharpless and DePinho, 1999). Furthermore, they are suppressed in
genetically reprogrammed and induced pluripotent cells and in embryonic stem cells
(Li et al., 2009c). Thus overall the products of the ARF locus are closely linked with
cell cycle regulation, cell senescence and apoptosis and differentiation. This is the
rationale for including the cyclin-dependent kinase inhibitors as a part of the discus-
sion of apoptosis signalling.

ARFs and Bmi-1 Function

The status of ARFs in cancer stem cells has received much attention in recent years.
It is regulated by p53. The expression of ARF is repressed by binding to p53. This
inactivation of ARF requires both HDACs and the Polycomb group proteins (Zeng
et al., 2011). Bmi-1 (the Polycomb group protein B lymphoma Mo-MLV insertion
region 1 homologue) negatively regulates the expression of the pro-apoptotic gene
Bim (Jagani et al., 2010). Bmi-1 is overexpressed in many cancers and is essential
for stem cell renewal. Hence there is much interest in the fact that Bmi-1 is a regu-
latory component of the PRC1 complex (see p. 169). The latter has been shown to
regulate the transcription of ARFs (Cao et al., 2011). Cell subpopulations capable
of self-renewal and tumorigenesis that could be CSCs displayed stem cell markers
CD166 and CD44 and were characterised by loss of expression of ARFs (Rath et al.,
2011). In mammary epithelium, suppression of the ARF locus restores Bmi-1 and
leads stem cell renewal and growth (Pietersen et al., 2008) and by implication of