Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Amino Acid Sequence

Animals

Carrier Proteins/*metabolism

Cell Fractionation

Cell Line

Cell Membrane/metabolism

*Cell Proliferation

Colon/cytology

Cyclin D1/*metabolism

Humans

Intestinal Mucosa/metabolism

Membrane Proteins/*metabolism

Mice

Mice

Inbred C57BL

Mitosis

PDZ Domains

Protein Binding

Protein Interaction Domains and Motifs

Protein Stability

Protein Transport

Recombinant Fusion Proteins/metabolism

Tight Junctions/*metabolism

Zonula Occludens Proteins

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)