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Vol. 17, Issue 8, 3569-3577, August 2006

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Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Laurent Guillemot^*, and Sandra Citi^*,

*Department of Molecular Biology, University of Geneva, CH-1211 Geneva, Switzerland; and Department of Biology, University of Padova, I-35121 Padova, Italy

Submitted February 9, 2006; Revised May 11, 2006; Accepted May 12, 2006
Monitoring Editor: Asma Nusrat

In mouse embryoid bodies, mutation of the tight junction protein cingulin results in changes in gene expression. Here, we studied the function of cingulin using a gene silencing approach in Madin-Darby canine kidney (MDCK) cells. Cingulin-depleted cells show higher protein and mRNA levels of claudin-2 and ZO-3, increased RhoA activity, activation of G₁/S phase transition, and increased cell density. The effects of cingulin depletion on claudin-2 expression, cell proliferation, and density are reversed by coexpression of either a dominant-negative form of RhoA (RhoAN19) or the Rho-inhibiting enzyme C3 transferase. However, the increase in ZO-3 protein and mRNA levels is not reversed by inhibition of either RhoA, p38, extracellular signal-regulated kinase (ERK), or c-Jun NH₂-terminal kinase (JNK), suggesting that cingulin modulates ZO-3 expression by a different mechanism. JNK is implicated in the regulation of claudin-2 levels independently of cingulin depletion and RhoA activity, indicating distinct roles of RhoA- and JNK-dependent pathways in the control of claudin-2 expression. Finally, cingulin depletion does not significantly alter the barrier function of monolayers and the overall molecular organization of tight junctions. These results provide novel insights about the mechanisms of cingulin function and the signaling pathways controlling claudin-2 expression in MDCK cells.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Sandra Citi ( sandra.citi{at}molbio.unige.ch)

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