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.

DOI: 10.1091/mbc.E10-08-0677

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Cite this paper

@inproceedings{Capaldo2011TightFZ, title={Tight function zonula occludens-3 regulates cyclin D1–dependent cell proliferation}, author={Christopher T. Capaldo and Stefan Koch and Michael H Kwon and Oskar Laur and Charles A Parkos and Asma Nusrat}, booktitle={Molecular biology of the cell}, year={2011} }