title: Cytoplasmic mislocalization of p27 and CDK2 mediates the anti-migratory and anti-proliferative effects of Nodal in human trophoblast cells.
abstract: p27(Kip1), a cyclin-dependent kinase (CDK) inhibitor, is a multi-functional protein that regulates various cellular activities. Trophoblast proliferation, migration and invasion are some of the key processes of placental development. We have recently reported that Nodal, a member of the transforming growth factor-β (TGF-β) superfamily, inhibits human trophoblast cell proliferation, migration and invasion. In the present study, we investigated the mechanism by which Nodal regulates trophoblast activities. We found that Nodal increased p27 mRNA and protein levels by enhancing their stability. Interestingly, Nodal signaling also induced nuclear export of p27 and CDK2. Cytoplasmic translocation of p27 induced by Nodal requires p27 phosphorylation at S10. In addition, Nodal enhanced the association of p27 with CDK2, CDK5 and a microtubule-destabilizing protein, stathmin, and induced stathmin phosphorylation at S25 and S38. Furthermore, Nodal increased tubulin stability as revealed by immunofluorescent staining of acetylated tubulin. Finally, silencing of p27 reversed the inhibitory effect of Nodal on trophoblast cell proliferation, migration and invasion. Taken together, our findings revealed a novel function of simultaneous p27 and CDK2 cytoplasmic mislocalization in mediating growth-factor-regulated cell proliferation, migration and invasion.
authors.affiliation: Department of Biology, York University, Toronto, ON, M3J 1P3, Canada.
authors.forename: Lubna
authors.initials: L
authors.lastname: Nadeem
authors.forename: Jelena
authors.initials: J
authors.lastname: Brkic
authors.forename: Yangchun Frank
authors.initials: YF
authors.lastname: Chen
authors.forename: Tung
authors.initials: T
authors.lastname: Bui
authors.forename: Sadia
authors.initials: S
authors.lastname: Munir
authors.forename: Chun
authors.initials: C
authors.lastname: Peng
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C501109:NOMO3 protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2