title: Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration.
abstract: Cell migration is a dynamic process that is central to a variety of physiological functions as well as disease pathogenesis. The modulation of cell migration by p27 (officially known as CDKN1B) has been reported, but the exact mechanism(s) whereby p27 interacts with downstream effectors that control cell migration have not been elucidated. By systematically comparing p27(+/+) mouse embryonic fibroblasts (MEFs) with genetically ablated p27(-/-) MEFs using wound-healing, transwell and time-lapse microscopic analyses, we provide direct evidence that p27 inhibits both directional and random cell migration. Identical results were obtained with normal and cancer epithelial cells using complementary knockdown and overexpression approaches. Additional studies revealed that overexpression of manganese superoxide dismutase (MnSOD, officially known as SOD2) and reduced intracellular oxidation played a key role in increased cell migration in p27-deficient cells. Furthermore, we identified signal transducer and activator of transcription 3 (STAT3) as the transcription factor responsible for p27-regulated MnSOD expression, which was further mediated by ERK- and ATF1-dependent transactivation of the cAMP response element (CRE) within the Stat3 promoter. Collectively, our data strongly indicate that p27 plays a crucial negative role in cell migration by inhibiting MnSOD expression in a STAT3-dependent manner.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Wei
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Nina Wu
authors.initials: NW
authors.lastname: Zhu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Urology and Pathology, New York University School of Medicine, and Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, NY 10010, USA.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA chuanshu.huang@nyumc.org.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D050796:STAT3 Transcription Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013482:Superoxide Dismutase
keywords: CRE; Cell migration; MnSOD; STAT3; p27
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