Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all

Abstract

The INK4b-ARF-INK4a locus encodes two members of the INK4 family of cyclin-dependent kinase inhibitors, p15(INK4b) and p16(INK4a), and a completely unrelated protein, known as ARF. All three products participate in major tumour suppressor networks that are disabled in human cancer and influence key physiological processes such as replicative senescence, apoptosis and stem-cell self-renewal. Transcription from the locus is therefore kept under strict control. Mounting evidence suggests that although the individual genes can respond independently to positive and negative signals in different contexts, the entire locus might be coordinately suppressed by a cis-acting regulatory domain or by the action of Polycomb group repressor complexes.

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…In addition, senescence also has roles in early embryogenesis and aging amongst other physiological processes (Munoz‐Espin & Serrano, 2014). The INK4/ARF locus encodes three proteins involved in the implementation of senescence: the cyclin‐dependent kinase inhibitors (CDKI) p16 INK4a and p15 INK4b and ARF, a regulator of p53 (Gil & Peters, 2006; Kim & Sharpless, 2006). In proliferating cells, the expression of the INK4/ARF locus is tightly controlled by the action of Polycomb repressive complexes (PRCs).…”

Cellular senescence impact on immune cell fate and function

“…One gene locus, namely CDKN2A, which encodes for two unrelated proteins p16 INK4a and p14/p19 ARF , is involved in this senescence‐induced cell cycle arrest (Krishnamurthy et al ., 2004). Indeed, by inhibiting cyclin‐dependent kinases (CDKs), p16 INK4a maintains the retinoblastoma family members (pRB, p107, and p130) in their transcriptionally repressive forms, thus preventing G1/S cell cycle progression (Gil & Peters, 2006). On the other hand, by interfering with MDM2 (mouse double minute 2)‐dependent degradation of p53, p14/p19 ARF controls p53/p21 WAF1 ‐induced G1 or G2 cell cycle arrest (Gil & Peters, 2006).…”

“…Indeed, by inhibiting cyclin‐dependent kinases (CDKs), p16 INK4a maintains the retinoblastoma family members (pRB, p107, and p130) in their transcriptionally repressive forms, thus preventing G1/S cell cycle progression (Gil & Peters, 2006). On the other hand, by interfering with MDM2 (mouse double minute 2)‐dependent degradation of p53, p14/p19 ARF controls p53/p21 WAF1 ‐induced G1 or G2 cell cycle arrest (Gil & Peters, 2006). Remarkably, using knockout mice models for this locus, it was possible to reveal that these senescence features could be associated with the terminal differentiation program in some specific cell types including keratinocytes (Paramio et al ., 2001; Bachoo et al ., 2002), chondrocytes (Philipot et al ., 2014), myofibers (Pajcini et al ., 2010), and also megakaryocytic cells (Muñoz‐Espín & Serrano, 2014).…”

Binding to nucleophosmin determines the localization of human and chicken ARF but not its impact on p53

“…For example, the chicken orthologue of the protein, p7 ARF , has no contribution from exon 2 because the splicing of exon 1b to exon 2 occurs in a different register to that used in mammals, and translation terminates abruptly at the end of exon 1b (Kim et al, 2003). We have therefore argued that the evolutionary pressure for exon sharing is unlikely to reflect the composition of the ARF protein and that its functional attributes are most likely specified by the sequences encoded by exon 1b (Gil and Peters, 2006).…”

“…The best understood function of ARF is its ability to inhibit the ubiquitin ligase activity of MDM2 (Gil and Peters, 2006;Sherr, 2006). In so doing, ARF stabilizes p53 resulting in the activation of p53 target genes, including that of the CDK inhibitor p21 CIP1 , and MDM2 itself.…”