title: Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 is Necessary for Normal Mitotic Progression.
abstract: Wip1 belongs to the protein phosphatase C (PP2C) family, of which expression is up-regulated by a number of external stresses, and serves as a stress modulator in normal physiological conditions. When overexpressed, premature dephosphorylation of stress-mediators by Wip1 results in abrogation of tumor surveillance, thus Wip1 acts as an oncogene. Previously, the functional regulation of Wip1 in cell-cycle progression by counteracting cellular G1 and G2/M checkpoint activity in response to DNA damage was reported. However, other than in stress conditions, the function and regulatory mechanism of Wip1 has not been fully determined. Herein, we demonstrated that protein regulation of Wip1 occurs in a cell cycle-dependent manner, which is directly governed by APC/C(Cdh1) at the end of mitosis. In particular, we also showed evidence that Wip1 phosphatase activity is closely associated with its own protein stability, suggesting that reduced phosphatase activity of Wip1 during mitosis could trigger its degradation. Furthermore, to verify the physiological role of its phosphatase activity during mitosis, we established doxycycline-inducible cell models, including a Wip1 wild type (WT) and phosphatase dead mutant (Wip1 DA). When ectopically expressing Wip1 WT, we observed a delay in the transition from metaphase to anaphase. In conclusion, these studies show that mitotic degradation of Wip1 by APC/C(Cdh1) is important for normal mitotic progression.
authors: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Korea.
authors: Ho-Chang
authors: HC
authors: Jeong
authors: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Korea.
authors: Na-Yeon
authors: NY
authors: Gil
authors: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Korea.
authors: Ho-Soo
authors: HS
authors: Lee
authors: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Korea.
authors: Seung-Ju
authors: SJ
authors: Cho
authors: National Cancer Center, Goyang-si, Gyeonggi-do, Korea.
authors: Kyungtae
authors: K
authors: Kim
authors: Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, Korea.
authors: Kwang-Hoon
authors: KH
authors: Chun
authors: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Korea.
authors: Hyeseong
authors: H
authors: Cho
authors: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Korea.
authors: Hyuk-Jin
authors: HJ
authors: Cha
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008938:Mitosis; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D059748:Proteolysis
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D004318:Doxycycline
keywords: ANAPHASE TRANSITION; APC/CCdh1; ATM; MITOSIS; MITOTIC PROGRESSION; Wip1