title: BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2.
abstract: BRCA2 germline mutations account for the majority of heredity breast and ovarian cancer. Besides its role in DNA damage repair, BRCA2 also plays an important role in cytokinesis, transcription regulation, and cancer cell proliferation. Recently, we reported that BRCA2 localizes to centrosomes as well as nuclei and the dysfunction of BRCA2 in a centrosome causes abnormalities in cell division. Here, we identified a nucleolar phosphoprotein, nucleophosmin (NPM), as a novel BRCA2-associated protein. We also detected the binding of BRCA2 to ROCK2, an effector of Rho small GTPase. Because it is known that ROCK2 binds to NPM at centrosomes, these 3 proteins may form a complex. NPM-binding region was within amino acids 639-1,000 of BRCA2. Exogenous expression of this BRCA2 region resulted in aberrant centrosome amplification and a high frequency of multinucleated cells. Our results suggested that a complex consisting of BRCA2, NPM, and ROCK2 maintains the numerical integrity of centrosomes and accurate cell division and that dysfunction of this regulation might be involved in the tumorigenesis of breast cancer.
authors.affiliation: Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hui-Feng
authors.initials: HF
authors.lastname: Wang
authors.forename: Katsuya
authors.initials: K
authors.lastname: Takenaka
authors.forename: Akira
authors.initials: A
authors.lastname: Nakanishi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Miki
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D019556:COS Cells; D018385:Centrosome; D002522:Chlorocebus aethiops; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D000090243:Nucleophosmin; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases