Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 21 (29), 4498-507

Multiple Interacting Domains Contribute to p14ARF Mediated Inhibition of MDM2

Affiliations

Multiple Interacting Domains Contribute to p14ARF Mediated Inhibition of MDM2

Paula A Clark et al. Oncogene.

Abstract

The small basic protein p14ARF, encoded by one of the alternative transcripts from the human INK4A/ARF locus, interferes with MDM2-mediated ubiquitination of the p53 tumour suppressor protein. The resultant stabilization of p53 leads to increased expression of p53-regulated genes, such as MDM2 itself and the cyclin-dependent kinase inhibitor p21(CIP1). Here we relate physical interactions between p14ARF and MDM2, as determined using synthetic peptides and systematic deletions of p14ARF, with consequential effects on p53 stabilization and transcriptional activity. The data imply that the amino terminal half of p14ARF, encoded by the alternative first exon (exon 1beta) contacts MDM2 through multiple domains that can independently impede MDM2-mediated degradation of p53, provided that they are localized in the cell nucleus. As well as identifying previously unrecognized functional domains, our findings offer an explanation for the relative paucity of missense mutations in exon 1beta in human tumours.

Similar articles

  • An N-terminal p14ARF Peptide Blocks Mdm2-dependent Ubiquitination in Vitro and Can Activate p53 in Vivo
    CA Midgley et al. Oncogene 19 (19), 2312-23. PMID 10822382.
    The p53 tumour suppressor protein is down-regulated by the action of Mdm2, which targets p53 for rapid degradation by the ubiquitin-proteasome pathway. The p14ARF protein …
  • P14ARF Promotes Accumulation of SUMO-1 Conjugated (H)Mdm2
    DP Xirodimas et al. FEBS Lett 528 (1-3), 207-11. PMID 12297306.
    p14ARF tumour suppressor stabilises and activates p53 by directly interacting with (H)Mdm2 [(human) murine double minute 2 homologue] and inhibiting its E3 ubiquitin liga …
  • Defining the Molecular Basis of Arf and Hdm2 Interactions
    B Bothner et al. J Mol Biol 314 (2), 263-77. PMID 11718560.
    Understanding the interaction of Arf and Hdm2 has recently become a central issue in cancer biology. In response to hyperproliferative signals, p14(Arf) stabilizes p53 by …
  • The MDM2-p53 Interaction
    UM Moll et al. Mol Cancer Res 1 (14), 1001-8. PMID 14707283. - Review
    Activation of the p53 protein protects the organism against the propagation of cells that carry damaged DNA with potentially oncogenic mutations. MDM2, a p53-specific E3 …
  • The ARF Tumour Suppressor
    SJ Gallagher et al. Int J Biochem Cell Biol 38 (10), 1637-41. PMID 16600663. - Review
    The ARF tumour suppressor is a product of the INK4a/ARF locus; a sequence that is frequently altered in human cancer. ARF is upregulated by oncogenic stimuli and is a cri …
See all similar articles

Cited by 15 PubMed Central articles

See all "Cited by" articles

MeSH terms

LinkOut - more resources

Feedback