Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation.
Nucleophosmin (NPM, B23) is an abundant nucleolar phosphoprotein involved in ribosome biogenesis, and interacts with tumor suppressor proteins p53 and Rb. Here we show that NPM is a UV damage response protein that undergoes nucleoplasmic redistribution and regulates p53 and HDM2 levels and their interaction. By utilizing RNAi approaches and analyses of endogenous and ectopically expressed proteins, we demonstrate that NPM binds HDM2 and acts as a negative regulator of p53-HDM2 interaction. Viral stress, enforced by expression of Kaposi's sarcoma virus K cyclin, causes NPM redistribution, K cyclin-NPM association, and p53 stabilization by dissociation of HDM2-p53 complexes. The results demonstrate novel associations of HDM2 and K cyclin with NPM and implicate NPM as a crucial controller of p53 through inhibition of HDM2.
Kurki
Sari
S
Haartman Institute and Molecular Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Helsinki, Finland.
Peltonen
Karita
K
Latonen
Leena
L
Kiviharju
Taija M
TM
Ojala
Päivi M
PM
Meek
David
D
Laiho
Marikki
M
D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism* / Q000528:radiation effects; D002478:Cells, Cultured; D016213:Cyclins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D034741:RNA, Small Interfering / Q000494:pharmacology; D025842:SUMO-1 Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects; D016335:Zinc Fingers
C113028:CCNK protein, human; D016213:Cyclins; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase