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, 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.
authors.affiliation: Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Ochocka
authors.forename: Petros
authors.initials: P
authors.lastname: Kampanis
authors.forename: Samantha
authors.initials: S
authors.lastname: Nicol
authors.forename: Nerea
authors.initials: N
authors.lastname: Allende-Vega
authors.forename: Miranda
authors.initials: M
authors.lastname: Cox
authors.forename: Lynnette
authors.initials: L
authors.lastname: Marcar
authors.forename: Diane
authors.initials: D
authors.lastname: Milne
authors.forename: Frances
authors.initials: F
authors.lastname: Fuller-Pace
authors.forename: David
authors.initials: D
authors.lastname: Meek
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C074856:FKBP3 protein, human; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase; D046988:Proteasome Endopeptidase Complex; D022021:Tacrolimus Binding Proteins