title: Slug is temporally regulated by cyclin E in cell cycle and controls genome stability.
abstract: The transcriptional repressor Slug is best known to control epithelial-mesenchymal transition (EMT) and promote cancer invasion/metastasis. In this study, we demonstrate that Slug is temporally regulated during cell cycle progression. At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. Non-phosphorylatable Slug is markedly stabilized at G1/S transition compared with wild-type Slug and greatly leads to downregulation of DNA synthesis and checkpoint-related proteins, including TOP1, DNA Ligase IV and Rad17, reduces cell proliferation, delays S-phase progression and contributes to genome instability. Our results indicate that Slug has multifaceted roles in cancer progression by controlling both EMT and genome stability.
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan.
authors.forename: W-L
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Huang
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kao
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: 1] Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan [2] Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: K-C
authors.initials: KC
authors.lastname: Li
authors.affiliation: 1] Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan [2] Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: S-L
authors.initials: SL
authors.lastname: Yu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: S-P
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: T-H
authors.initials: TH
authors.lastname: Hsiao
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan [3] NTU Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: P-C
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan.
authors.forename: T-M
authors.initials: TM
authors.lastname: Hong
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D019927:Cyclin E; D007976:Leupeptins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde