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

Anna Maria Ochocka; Petros Kampanis; Samantha Nicol; Nerea Allende-Vega; Miranda Cox; Lynnette Marcar; Diane Milne; Frances Fuller-Pace; David Meek

doi:10.1016/j.febslet.2009.01.009

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

Anna Maria Ochocka
, Petros Kampanis
, Samantha Nicol
, Nerea Allende-Vega
, Miranda Cox
, Lynnette Marcar
, Diane Milne
, Frances Fuller-Pace
, David Meek

Research output: Contribution to journal › Article › peer-review

60 Citations (Scopus)

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, 25 kDa 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. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Original language	English
Pages (from-to)	621-626
Number of pages	6
Journal	FEBS Letters
Volume	583
Issue number	4
DOIs	https://doi.org/10.1016/j.febslet.2009.01.009
Publication status	Published - 18 Feb 2009

Keywords

FKBP25
MDM2
p53
E3 ligase
Ubiquitylation
Degradation
CULTURED-CELLS
IN-VITRO
PROTEIN

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10.1016/j.febslet.2009.01.009

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

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, 25 kDa 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. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.",

keywords = "FKBP25, MDM2, p53, E3 ligase, Ubiquitylation, Degradation, CULTURED-CELLS, IN-VITRO, PROTEIN",

author = "Ochocka, \{Anna Maria\} and Petros Kampanis and Samantha Nicol and Nerea Allende-Vega and Miranda Cox and Lynnette Marcar and Diane Milne and Frances Fuller-Pace and David Meek",

year = "2009",

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doi = "10.1016/j.febslet.2009.01.009",

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T1 - FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53

AU - Ochocka, Anna Maria

AU - Kampanis, Petros

AU - Nicol, Samantha

AU - Allende-Vega, Nerea

AU - Cox, Miranda

AU - Marcar, Lynnette

AU - Milne, Diane

AU - Fuller-Pace, Frances

AU - Meek, David

PY - 2009/2/18

Y1 - 2009/2/18

N2 - 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, 25 kDa 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. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

AB - 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, 25 kDa 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. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

KW - FKBP25

KW - MDM2

KW - p53

KW - E3 ligase

KW - Ubiquitylation

KW - Degradation

KW - CULTURED-CELLS

KW - IN-VITRO

KW - PROTEIN

U2 - 10.1016/j.febslet.2009.01.009

DO - 10.1016/j.febslet.2009.01.009

M3 - Article

C2 - 19166840

SN - 0014-5793

VL - 583

SP - 621

EP - 626

JO - FEBS Letters

JF - FEBS Letters

IS - 4

ER -

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

Abstract

Keywords

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