Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 41 (5), 381-389

Regulatory Network of ARF in Cancer Development


Regulatory Network of ARF in Cancer Development

Aram Ko et al. Mol Cells.


ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the ARF gene is a frequent target of genetic and epigenetic alterations including promoter hyper-methylation or gene deletion. However, as many cancer cells still express ARF, pathways that negatively modulate transcriptional or post-translational regulation of ARF could be potentially important means for cancer cells to induce cellular proliferation. These recent findings of regulators affecting ARF protein stability along with its low levels in numerous human cancers indicate the significance of an ARF post-translational mechanism in cancers. Novel findings of regulators stimulating or suppressing ARF function would provide new therapeutic targets to manage cancer- and senescence-related diseases. In this review, we present the current knowledge on the regulation and alterations of ARF expression in human cancers, and indicate the importance of regulators of ARF as a prognostic marker and in potential therapeutic strategies.

Keywords: ARF; E3 ligases; post-translational modification; transcriptional regulation; tumorigenesis.


Fig. 1
Fig. 1. The INK4a/ARF/INK4b locus and tumor suppressive functions of ARF
The INK4a/ARF/INK4b locus encodes potent tumor suppressors including p15ink4b, p16ink4a and p14ARF. ARF stimulates cellular senescence and apoptosis through p53-dependent or -independent pathway, thus suppressing the tumor formation.
Fig. 2
Fig. 2. Post-translational regulation of ARF
E3 ubiquitin ligases, SIVA1, MKRN1 and ULF induces ubiquitination dependent pro-teasomal degradation of ARF, which is reversed by deubiquitinase, USP10-mediated deubiquitination. CHIP and HSP90 cooperatively stimulates ubiquitin-independent lysosomal degradation of ARF.

Similar articles

  • The ARF Tumor Suppressor: Keeping Myc on a Leash
    MA Gregory et al. Cell Cycle 4 (2), 249-52. PMID 15655352.
    The ARF tumor suppressor protein acts in a checkpoint that guards against unscheduled cellular proliferation in response to oncogenic signaling. Deregulated expression of …
  • Abnormal MDMX Degradation in Tumor Cells Due to ARF Deficiency
    X Li et al. Oncogene 31 (32), 3721-32. PMID 22120712.
    MDMX is a heterodimeric partner of MDM2 and a critical regulator of p53. The MDMX level is generally elevated in tumors with wild-type p53 and contributes to p53 inactiva …
  • p16Ink4a or p19Arf Loss Contributes to Tal1-induced Leukemogenesis in Mice
    JA Shank-Calvo et al. Oncogene 25 (21), 3023-31. PMID 16407836.
    Analysis of the INK4A/ARF locus in human T-ALL patients revealed frequent deletions in exon 2, the exon common to both p16(INK4A) and p14(ARF). Other studies have describ …
  • Dynamics in the p53-Mdm2 Ubiquitination Pathway
    CL Brooks et al. Cell Cycle 3 (7), 895-9. PMID 15254415. - Review
    The tumor suppressor p53 is highly regulated under various states of cellular stress. p53 stability is predominantly regulated through the ubiquitin-proteasomal pathway b …
  • Involvement of the INK4a/Arf Gene Locus in Senescence
    CJ Collins et al. Aging Cell 2 (3), 145-50. PMID 12882406. - Review
    The INK4a/ARF locus encodes two proteins whose expression limits cellular proliferation. Whilst the biochemical activities of the two proteins appear very different, they …
See all similar articles

Cited by 3 PubMed Central articles


    1. Adhikary S., Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 2005;6:635–645. - PubMed
    1. Aslanian A., Iaquinta P.J., Verona R., Lees J.A. Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Genes Dev. 2004;18:1413–1422. - PMC - PubMed
    1. Berggren P., Kumar R., Sakano S., Hemminki L., Wada T., Steineck G., Adolfsson J., Larsson P., Norming U., Wijkstrom H., et al. Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res. 2003;9:235–242. - PubMed
    1. Bouchard C., Lee S., Paulus-Hock V., Loddenkemper C., Eilers M., Schmitt C.A. FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev. 2007;21:2775–2787. - PMC - PubMed
    1. Bracken A.P., Kleine-Kohlbrecher D., Dietrich N., Pasini D., Gargiulo G., Beekman C., Theilgaard-Monch K., Minucci S., Porse B.T., Marine J.C., et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007;21:525–530. - PMC - PubMed

MeSH terms