title: Knockdown of Sec8 promotes cell-cycle arrest at G1/S phase by inducing p21 via control of FOXO proteins.
abstract: p21(Cip1) protein inhibits the activity of cyclins at the G(1) checkpoint and influences transition of cells from the G(1) to the S phase of the cell cycle. Moreover, expression of members of the FOXO family (active form of forkhead transcription factors of the O class) in dividing cells promotes cell-cycle arrest at the G(1)/S boundary via regulation of p21(Cip1). Recently, the exocyst complex, including Sec8, has been implicated in various roles independent of its role in secretion, such as cell migration, invadopodia formation, cytokinesis, glucose uptake and neural development. Given the essential roles of the exocyst complex in cellular and developmental processes, disruption of its function may be involved in various diseases such as cancer, diabetes and neuronal disorders. However, the relationship between Sec8 and the cell cycle remains to be elucidated. In this study, knockdown of Sec8 inhibited cell growth and promoted cell-cycle arrest at the G(1)/S phase by control of p21 expression and retinoblastoma protein phosphorylation. Furthermore, Sec8 regulated FOXO family proteins via ubiquitin-proteasome degradation by regulating the expression of the murine double minute 2 (Mdm2) protein but not S-phase kinase-associated protein 2 (Skp2).
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine, School of Medicine, Yamagata University, Japan; Department of Dentistry, Oral and Maxillofacial Surgery, Plastic and Reconstructive Surgery, Faculty of Medicine, School of Medicine, Yamagata University, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Mituyoshi
authors.initials: M
authors.lastname: Iino
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D016196:S Phase / Q000235:genetics / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C489607:EXOC4 protein, human; D051858:Forkhead Transcription Factors; D033921:Vesicular Transport Proteins
keywords: FOXOs; Mdm2; Sec8; cell-cycle arrest; p21