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The INK4a/ARF network in tumour suppression

Nature Reviews Molecular Cell Biology volume 2, pages 731–737 (2001)Cite this article

Abstract

The retinoblastoma protein (RB) and p53 transcription factor are regulated by two distinct proteins that are encoded by the INK4a/ARF locus. Genes encoding these four tumour suppressors are disabled, either in whole or in part, in most human cancers. A complex signalling network that interconnects the activities of RB and p53 monitors oncogenic stimuli to provide a cell-autonomous mode of tumour surveillance.

Key Points

  • The human INK4a/ARF locus encodes two distinct tumour-suppressor proteins — p16INK4a and p14ARF (p19Arf in the mouse) — in part, through the utilization of alternative reading frames. p16INK4a and p14ARF function by promoting the activities of the retinoblastoma protein (RB) and p53 transcription factor, respectively.

  • p16INK4a is an inhibitor of the cyclin D-dependent kinases, CDK4 and CDK6, whereas p14ARF antagonizes the function of the p53 negative regulator, HDM2 (Mdm2 in the mouse).

  • p16INK4a blocks cell cycle progression through two mechanisms. It disrupts and inhibits holoenzyme complexes containing D-type cyclins and either CDK4 or CDK6. It also mobilizes bound Cip/Kip proteins, which indirectly blocks the activities of cyclin E- and A-dependent CDK2.

  • Although four different INK4 proteins act as potent inhibitors of cyclin D-dependent kinases, p16INK4a plays the most prominent role in tumour suppression, presumably because of its unique pattern of expression.

  • Selective disruption of either Ink4a or Arf coding sequences in the mouse germ line shows that both genes act as tumor suppressors and have roles in cellular senescence.

  • Specific combinations of genetic lesions that affect the Ink4a and Arf genes on homologous chromosomes predispose to many different forms of cancer.

  • Arf is activated by oncogenic signals, such as Myc overexpression or constitutive Ras activation. By activating p53, p19Arf diverts incipient cancer cells to alternative fates — either to p53-dependent growth arrest or apoptosis.

  • A complex signalling network — consisting of many branch points, feed-forward and feedback controls — connects the activities of RB and p53. Disruption of this signalling network could be an essential feature of the life history of cancer cells.

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Figure 1: The Ink4a/Arf locus.
Figure 2: The Ink4 family.
Figure 3: Activity of p16INK4a and CDK inhibitors.
Figure 4: A signalling network central to tumour suppression.

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Acknowledgements

The author gratefully thanks M. F. Roussel and B. Schulman for insightful comments on the manuscript. C. J. S. is an Investigator of Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Tumor Cell Biology, Howard Hughes Medical Institute, St Jude Children's Research Hospital, 332 North Lauderdale, Tennessee, 38105, Memphis, USA

    Charles J. Sherr

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DATABASE LINKS

Locuslink:

ATM

CDK2

CDK4

CDK6

cyclin D1

cyclin D2

cyclin D3

cyclin E

E2F transcription factors

HDM2

p15INK4b

p16INK4a

p18INK4c

p19INK4d

p73

INK4a

 Mouse Genome Informatics:

Bmi1

Ink4b

Ink4c

Ink4d

p19Arf

p21Cip1

p27Kip1

v-Abl

 Swiss-prot:

p53

Glossary

E2F TRANSCRIPTION FACTOR

A heterodimeric transcription factor that is composed of an E2F subunit (1–6) and either DP-1 or DP-2.

ARF

An alternative reading-frame protein of INK4a/ARF. The locus encodes p19Arf in the mouse and p14ARF in humans.

E3 UBIQUITIN PROTEIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

DP-1 AND DP-2

Proteins that dimerize with E2F subunits, enabling E2F–DP complexes to bind to DNA.

INK4 FAMILY

A family of genes that encode an inhibitor of CDK4. Four such genes — designated in order of discovery — are INK4a, INK4b, INK4c and INK4d. These encode polypeptides of 15–19 kDa and are designated p16INK4a, p15INK4b, p18INK4c and p19INK4d, respectively.

CIP/KIP FAMILY

A family of genes that includes p21Cip1, p27Kip1 and p57Kip2. Cip, CDK-inhibitory protein; Kip, kinase-inhibitory protein.

EXTRAMEDULLARY HAEMATOPOIESIS

Blood formation at sites outside of the bone marrow, usually in the spleen or liver.

EARLY PASSAGE

Primary cells explanted into culture, when grown and serially transferred, eventually undergo replicative arrest. Cells at early passage maintain a more robust proliferative capacity, whereas those at late passage replicate less well.

PLASMACYTOMA

A tumour mass, usually solitary, containing immunoglobulin-producing plasma cells. The presence of many such disseminated tumours, usually in bone, is called multiple myeloma.

IMMUNOGLOBULIN PROMOTER–ENHANCER

Regulatory sequences of genes that encode heavy (μ) or light (κ or λ) immunoglobulin polypeptides that assemble to form antibodies. In B-cell tumours, these regulatory sequences are translocated and fused to other genes, including the Myc oncogene.

HAPLO-INSUFFICIENCY

A state in which loss of only one of two alleles of a gene detectably disables its function.

RHABDOMYOSARCOMA

Malignant tumour arising from skeletal muscle.

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Sherr, C. The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2, 731–737 (2001). https://doi.org/10.1038/35096061

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