Zona occludens-2 inhibits cyclin D1 expression and cell proliferation and exhibits changes in localization along the cell cycle

• Published in: Molecular biology of the cell 2009-02, Vol.20 (3), p.1102-1117
• Main Authors: Tapia, Rocio, Huerta, Miriam, Islas, Socorro, Avila-Flores, Antonia, Lopez-Bayghen, Esther, Weiske, Jörg, Huber, Otmar, González-Mariscal, Lorenza
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; beta Catenin - metabolism; Cell Cycle; Cell Line; Cell Proliferation; Cyclin D1 - genetics; Cyclin D1 - metabolism; Dogs; Down-Regulation; Gene Expression Regulation; Glycogen Synthase Kinase 3 - metabolism; Humans; Membrane Proteins - metabolism; Models, Biological; Phosphoserine - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Processing, Post-Translational; Protein Transport; RNA, Messenger - genetics; RNA, Messenger - metabolism; Subcellular Fractions - metabolism; Transfection; Zonula Occludens-2 Protein
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.e08-03-0277

Here, we have studied the effect of the tight junction protein zona occludens (ZO)-2 on cyclin D1 (CD1) protein expression. CD1 is essential for cell progression through the G1 phase of the cell cycle. We have found that in cultures of synchronized Madin-Darby canine kidney cells, ZO-2 inhibits cell proliferation at G0/G1 and decreases CD1 protein level. These effects occur in response to a diminished CD1 translation and an augmented CD1 degradation at the proteosome triggered by ZO-2. ZO-2 overexpression decreases the amount of Glycogen synthase kinase-3beta phosphorylated at Ser9 and represses beta-catenin target gene expression. We have also explored the expression of ZO-2 through the cell cycle and demonstrate that ZO-2 enters the nucleus at the late G1 phase and leaves the nucleus when the cell is in mitosis. These results thus explain why in confluent quiescent epithelia ZO-2 is absent from the nucleus and localizes at the cellular borders, whereas in sparse proliferating cultures ZO-2 is conspicuously present at the nucleus.