FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53.
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.
Ochocka
Anna Maria
AM
Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom.
Kampanis
Petros
P
Nicol
Samantha
S
Allende-Vega
Nerea
N
Cox
Miranda
M
Marcar
Lynnette
L
Milne
Diane
D
Fuller-Pace
Frances
F
Meek
David
D
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
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