title: Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation.
abstract: Coordinated regulation of cell proliferation is vital for epithelial tissue homeostasis, and uncontrolled proliferation is a hallmark of carcinogenesis. A growing body of evidence indicates that epithelial tight junctions (TJs) play a role in these processes, although the mechanisms involved are poorly understood. In this study, we identify and characterize a novel plasma membrane pool of cyclin D1 with cell-cycle regulatory functions. We have determined that the zonula occludens (ZO) family of TJ plaque proteins sequesters cyclin D1 at TJs during mitosis, through an evolutionarily conserved class II PSD-95, Dlg, and ZO-1 (PDZ)-binding motif within cyclin D1. Disruption of the cyclin D1/ZO complex through mutagenesis or siRNA-mediated suppression of ZO-3 resulted in increased cyclin D1 proteolysis and G(0)/G(1) cell-cycle retention. This study highlights an important new role for ZO family TJ proteins in regulating epithelial cell proliferation through stabilization of cyclin D1 during mitosis.
authors.affiliation: Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Capaldo
authors.forename: Stefan
authors.initials: S
authors.lastname: Koch
authors.forename: Michael
authors.initials: M
authors.lastname: Kwon
authors.forename: Oskar
authors.initials: O
authors.lastname: Laur
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002458:Cell Fractionation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology; D019938:Cyclin D1 / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D054731:PDZ Domains; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D062825:Zonula Occludens Proteins
chemical_list: C530104:CCND1 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; C111873:TJP3 protein, human; D062825:Zonula Occludens Proteins; D019938:Cyclin D1