title: Lats1 suppresses centrosome overduplication by modulating the stability of Cdc25B.
abstract: Numerical aberration of the centrosome results in chromosome missegregation, eventually leading to chromosomal instability, a hallmark of human tumor malignancy. Large tumor suppressors 1 and 2 (Lats1 and Lats2) are central kinases in the Hippo pathway and regulate development and tumorigenesis by coordinating the balance between cell proliferation and apoptosis. Importantly, Lats1 and Lats2 also play pivotal roles in cell cycle checkpoint and mitosis. The Lats proteins localize at centrosomes, but their centrosomal functions remain elusive. Here, we generated Lats1-null knockout (Lats1(-/-)) mice and established Lats1-null mouse embryonic fibroblasts (MEFs). In Lats1(-/-) MEFs, centrosomes were markedly overduplicated, leading to severe mitotic defects such as chromosome missegregation and cytokinesis failure. We also found that Lats1 physically interacts with Cdc25B phosphatase that localizes both at the centrosome and in the nucleus and regulates the linkage between the centrosome cycle and mitotic progression. Although Lats1 did not phosphorylate Cdc25B, loss of Lats1 in MEFs caused abnormal accumulation of Cdc25B protein and hyperactivation of Cdk2 toward nucleophosmin (NPM/B23), one of the licensing factors involved in centriole duplication. Taken together, these data suggest that Lats1 regulates Cdc25B protein level and subsequent Cdk2 activity, thereby suppressing centrosome overduplication during interphase.
authors.affiliation: Department of Molecular Genetics Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mukai
authors.affiliation: Department of Molecular Genetics Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Yabuta
authors.affiliation: Department of Molecular Genetics Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Molecular Genetics Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Miura
authors.affiliation: Animal Resource Development Unit, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.|Genetic Engineering Team, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Animal Resource Development Unit, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Molecular Genetics Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
mesh_terms: D000818:Animals; D002455:Cell Division; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D048749:Cytokinesis; D016195:G2 Phase; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D055550:Protein Stability; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000090243:Nucleophosmin; C490501:Lats1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2; C517006:Cdc25b protein, mouse; D020687:cdc25 Phosphatases