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

Nature Reviews Molecular Cell Biology volume 7, pages 667–677 (2006)Cite this article

Key Points

  • The INK4b–ARF–INK4a locus encodes three proteins that are implicated in senescence and tumour suppression by virtue of their effect on the retinoblastoma protein (pRb) and p53 pathways.

  • Senescence is an important mechanism of tumour suppression that protects against unrestrained cell proliferation. There is growing evidence that senescence occurs in vivo in pre-malignant lesions.

  • The unusual evolution of the INK4b–ARF–INK4a locus would be consistent with a need for co-regulation in response to hyperproliferative signals.

  • An extensive list of factors is reported to activate expression of one or more of the genes encoded by the locus, in different contexts. Activators are likely to engage senescence, and therefore the oncogenic potential of these agents is only revealed in cells in which the defences have been breached.

  • Repressors of the INK4b–ARF–INK4a locus are likely to register as oncoproteins because they undermine the cell's capacity to become senescent.

  • The locus is regulated by members of the Polycomb group of transcriptional repressors that are implicated in cell-fate decisions and the maintenance of stem-cell identity.

Abstract

The INK4b–ARF–INK4a locus encodes two members of the INK4 family of cyclin-dependent kinase inhibitors, p15INK4b and p16INK4a, 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.

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Figure 1: Organization of the INK4b–ARF–INK4a locus in different species.
Figure 2: Activators and repressors of the INK4b–ARF–INK4a locus.

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Authors and Affiliations

  1. Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, W12 0NN, UK

    Jesús Gil

  2. Molecular Oncology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Gordon Peters

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  1. Jesús Gil
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Glossary

Senescence

A state of apparently permanent cell-cycle arrest that a cell adopts in the face of aberrant proliferative signals, intracellular stress or DNA damage.

Tumour suppressor

A gene whose loss of function contributes to cancer progression. Mutations in tumour suppressor genes are generally recessive and tumours arise when both copies of the gene are inactivated; for example, by deletion of the normal allele.

Epigenetic

Effects on the patterns of gene expression that are heritable through cell division without altering the genetic information carried in the cellular DNA.

Oncogene

A gene that contributes to cancer progression as a consequence of overexpression or of dominantly acting mutations that alter the activity or specificity of the gene product.

Polycomb group complexes

A group of multi-component protein complexes, first described in Drosophila melanogaster, that establish regions of chromatin in which gene expression is repressed.

Cyclin-dependent kinases

A family of serine–threonine protein kinases whose catalytic activity depends on their association with a cyclin subunit. They are involved in regulating cell-cycle progression.

Ankyrin repeat

A structural motif that comprises repeated modules of ∼33 amino acids that form a series of anti-parallel helix–loop–helix domains linked by β-hairpin loops. The motif was first identified in the protein ankyrin but is found in many other proteins with diverse functions.

INK4 proteins

A group of small (15–19 kDa) ankyrin-repeat proteins that bind specifically to the cyclin-dependent kinases CDK4 and CDK6, and block their association with regulatory D cyclins.

CIP/KIP family

A family of cyclin-dependent kinase inhibitors (designated p21CIP1, p27KIP1 and p57KIP2 in human cells) that bind to cyclin D-, cyclin E and cyclin A-dependent kinase complexes.

RAS

First identified in retroviruses that induce rat sarcomas (hence the name), the RAS genes encode G proteins that function in diverse signal transduction pathways and sustain activating point mutations in a high proportion of human cancers.

RAF–MEK–ERK

A kinase cascade that represents one of the major signal transduction pathways downstream of RAS, culminating in the phosphorylation of ERK (extracellular signal-regulated kinase). ERKs are classed as MAP kinases (mitogen-activated protein kinases), MEK is a MAPK kinase (MAPKK) and RAF is a MAPKK kinase.

Naevi

Raised, red/brown areas of skin, commonly referred to as moles, that represent benign precursors of melanomas.

p38 family

The four members of the p38 family, which are also known as stress-activated protein kinases (SAPKs), are a group of MAP kinases that are activated following exposure to cytokines, heat shock, high osmolarity and other cellular stresses.

MYC

MYC is a transcription factor that binds to DNA (at Ebox elements) as part of a heterodimeric complex with MAX. The gene is frequently overexpressed in human cancers as a consequence of DNA amplification, chromosomal translocation or mutations in the coding domain.

E-box element

A hexanucleotide sequence (CACGTG) that forms the core of promoter elements that are recognized by various basic helix–loop–helix (bHLH) transcription factors, including MYC and E2A.

BMI1

Initially identified as a common site of proviral integration in Moloney-virus-induced Bcell lymphomas, the BMI1 gene product was subsequently recognized as a member of the Polycomb group and a repressor of INK4a–ARF.

MDM2

Located on a mouse double minute (hence the name MDM) chromosome, the oncogene MDM2 encodes an E3 ubiquitin ligase that promotes the proteasome-mediated destruction of p53 and is transcriptionally activated by p53.

E2F family

A group of transcription factors that control the expression of genes that are involved in cell-cycle progression, by acting either as transcriptional repressors, in conjunction with members of the retinoblastoma family or as transcriptional activators.

AP1 family

Originally defined as 'activator protein-1', the generic term AP1 refers to a family of heterodimeric transcription factors that comprises members of the FOS (FOS, FRA1, FRA2), JUN (c-JUN, JUNB, JUNC, JUND) and ATF families.

ID proteins

A family of transcriptional regulators that lack the basic domain that is present in basic helix–loop–helix (bHLH) proteins and are therefore unable to bind to DNA. They function as dominant-negative inhibitors of certain bHLH proteins.

Basic helix–loop–helix domain

A protein structure motif that is found in various transcription factors, and that consists of a basic domain, which is responsible for sequence-specific DNA binding, followed by a helix–loop–helix domain that functions as a dimerization interface.

POZ/BTB domain

A protein–protein interaction domain that is found in various Pox virus and zinc-finger proteins. POZ domains from several zinc-finger proteins have been shown to mediate transcriptional repression and to interact with components of histone deacetylase corepressor complexes.

Chromodomain

A protein domain that is conserved in a wide number of chromatin-interacting proteins. The chromodomain is involved in binding to specific methylated lysine residues in the histone tails.

T-box proteins

The T-box family of transcription factors are involved in cell-fate decisions during development and contain a region (the T box) that is required for binding to the DNA consensus sequence TCACACCT.

CDC6

A cell-cycle-regulated protein that binds to origins of DNA replication and is involved in ensuring that DNA replication occurs only once during cell division.

Histone deacetylase

An enzyme that removes the acetyl groups from core histones that are generally associated with transcriptionally active chromatin. Deacetylation of the histone tails can allow access to histone methyltransferases that establish repressive chromatin.

Heterochromatin

A highly condensed and transcriptionally less active form of chromatin that occurs at defined sites, such as centromeres, silencer DNA elements or telomeres.

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Gil, J., Peters, G. Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7, 667–677 (2006). https://doi.org/10.1038/nrm1987

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