title: IKK-β/NF-κB p65 mediates p27(Kip1) protein degradation in arsenite response.
abstract: p27(Kip1) is a potent inhibitor of the cyclin-dependent kinases that drive G1 to S phase transition. Since deregulation of p27(Kip1) is found in many malignancies and is associated with the poor prognosis, elucidation of the molecular bases for regulation of p27(Kip1) expression is of great significance, not only in providing insight into the understanding of biological p27(Kip1), but also in the development of new cancer therapeutic tactics. We here explored the inhibitory regulation of IKKβ on p27(Kip1) expression following arsenite exposure. We found that although the basal level of p27(Kip1) expression in the IKKβ(-/-) cells is much lower than that in the IKKβ(+/+) cells, the deletion of IKKβ in the MEFs led to a marked increase in p27(Kip1) protein induction due to arsenite exposure in comparison to that in the IKKβ(+/+) cells. The IKKβ regulatory effect on p27(Kip1) expression was also verified in the IKKβ(-/-) and IKKβ(-/-) cells with IKKβ reconstitutional expression, IKKβ(-/-) (IKKβ). Further studies indicated that IKKβ-mediated p27(Kip1) downregulation occurred at protein degradation level via p65-dependent and p50-independent manner. Moreover, the results obtained from the comparison of arsenite-induced GSK3β activation among transfectants of WT, IKKβ(-/-) and IKKβ(-/-) (IKKβ), and the utilization of GSKβ shRNA, demonstrated that IKKβ regulation of p27 protein degradation was mediated by GSK3β following arsenite exposure.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States; Pathology Department, Wuhan University, 185 Donghu Rd., Wuhan, Hubei 430071, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jian
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Physiology Department, Wuhan University, 185 Donghu Rd., Wuhan, Hubei 430071, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States. Electronic address: chuanshu.huang@nyumc.org.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018053:Arsenites; C493961:Cdkn1b protein, mouse; D052002:NF-kappa B p50 Subunit; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D050760:Cyclin-Dependent Kinase Inhibitor p27; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D038362:Glycogen Synthase Kinase 3; C015001:arsenite
keywords: Arsenite; GSK; IKKβ; NF-κB; p27(Kip1) protein degradation
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