FEBS Letters
Volume 583, Issue 4 , Pages 621-626, 18 February 2009

FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53

Edited by Angel Nebreda

  • Anna Maria Ochocka

      Affiliations

    • Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • Petros Kampanis

      Affiliations

    • Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • Samantha Nicol

      Affiliations

    • Centre of Oncology and Molecular Medicine, Ninewells Hospital and Medical School, University of Dundee, Level 6, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • Nerea Allende-Vega

      Affiliations

    • Centre of Oncology and Molecular Medicine, Ninewells Hospital and Medical School, University of Dundee, Level 6, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • Miranda Cox

      Affiliations

    • Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • Lynnette Marcar

      Affiliations

    • Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • Diane Milne

      Affiliations

    • Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • Frances Fuller-Pace

      Affiliations

    • Centre of Oncology and Molecular Medicine, Ninewells Hospital and Medical School, University of Dundee, Level 6, University of Dundee, Dundee DD1 9SY, United Kingdom
    • ,
  • David Meek

      Affiliations

    • Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom
    • Corresponding Author InformationCorresponding author. Fax: +44 1382 669993.

Received 5 November 2008; received in revised form 17 December 2008; accepted 11 January 2009. published online 21 January 2009.

Abstract 

The p53 tumour suppressor protein is tightly controlled by the E3 ubiquitin ligase, mouse double minute 2 (MDM2), but maintains MDM2 expression as part of a negative feedback loop. We have identified the immunophilin, 25kDa FK506-binding protein (FKBP25), previously shown to be regulated by p53-mediated repression, as an MDM2-interacting partner. We show that FKBP25 stimulates auto-ubiquitylation and proteasomal degradation of MDM2, leading to the induction of p53. Depletion of FKBP25 by siRNA leads to increased levels of MDM2 and a corresponding reduction in p53 and p21 levels. These data are consistent with the idea that FKBP25 contributes to regulation of the p53-MDM2 negative feedback loop.

Structured summary

MINT-6823686:

MDM2 (uniprotkb:Q00987) physically interacts (MI:0218) with FKBP25 (uniprotkb:Q00688) by anti bait coimmunoprecipitation (MI:0006)

MINT-6823707, MINT-6823722:

MDM2 (uniprotkb:Q00987) physically interacts (MI:0218) with FKBP25 (uniprotkb:Q62446) by pull down (MI:0096)

MINT-6823775:

P53 (uniprotkb:Q04637) physically interacts (MI:0218) with MDM2 (uniprotkb:Q00987) by anti bait coimmunoprecipitation (MI:0006)

MINT-6823735, MINT-6823749:

FKBP25 (uniprotkb:Q62446) binds (MI:0407) to MDM2 (uniprotkb:Q00987) by pull down (MI:0096)

MINT-6823761:

Ubiquitin (UNIPROTKB:62988)P physically interacts (MI:0218) with MDM2 (uniprotkb:Q00987) by pull down (MI:0096)

MINT-6823669:

MDM2 (uniprotkb:Q00987) physically interacts (MI:0218) with FKBP25 (uniprotkb:Q00688) by two hybrid (MI:0018)

Abbreviations: MDM2, mouse double minute 2, FKBP25, 25kDa FK506-binding protein, PPI, peptidyl-prolyl isomerase

Keywords: FKBP25, MDM2, p53, E3 ligase, Ubiquitylation, Degradation

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PII: S0014-5793(09)00034-9

doi:10.1016/j.febslet.2009.01.009

FEBS Letters
Volume 583, Issue 4 , Pages 621-626, 18 February 2009

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