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J. Biol. Chem., Vol. 279, Issue 35, 36931-36942, August 27, 2004

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Connexin43 Interacts with NOV

A POSSIBLE MECHANISM FOR NEGATIVE REGULATION OF CELL GROWTH IN CHORIOCARCINOMA CELLS^*

Alexandra Gellhaus, Xuesen Dong, Sven Propson, Karen Maass¶, Ludger Klein-Hitpass||, Mark Kibschull, Otto Traub¶, Klaus Willecke¶, Bernard Perbal**, Stephen J. Lye, and Elke Winterhager

From the Institute of Anatomy and ^||Cell Biology, University Hospital Essen, 55 Hufelandstrasse, 45122 Essen, Germany, Department of Physiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada, ^¶Institute of Genetics, University of Bonn, 53117 Bonn, Germany, and ^**Laboratoire d'Oncologie Virale et Moleculaire, UFR de Biochimie, Université Paris, 75005 Paris, France

The gap junction protein connexin43 (Cx43) is thought to be involved in growth control in several tissues. Using the doxycycline inducible tet-on system, we generated human malignant trophoblast Jeg3 cells transfected with either Cx40, Cx43, or C-terminal truncated Cx43 (trCx43). Cx43, but not Cx40 or trCx43, displayed a reduced cell growth of Jeg3 cells in vitro and tumor growth in nude mice, suggesting a role of the C terminus of Cx43 in growth regulation. Using gene array analysis, the growth regulator NOV (CCN3), a member of the CCN gene family, was found to be up-regulated only in the Cx43-transfected cells. Validation by reverse transcriptase-PCR confirmed an up-regulation of the NOV transcript exclusively upon Cx43 induction. In contrast to Cx40 or trCx43, induction of Cx43 led to a switch in localization of NOV from the nucleus to the cell membrane, where it is colocalized with Cx43. Coimmunoprecipitation showed a binding of NOV to the C terminus of Cx43 in vitro as well as in transfected cells. Jeg3 cells transfected only with NOV revealed that NOV itself acts as a growth regulator. We suggest that Cx43 is able to regulate cell growth via an up-regulation of NOV transcription, a change in localization of the NOV protein and a binding of NOV to the C terminus of Cx43.

Received for publication, April 13, 2004 , and in revised form, May 25, 2004.

^* This work was supported by Mildred Scheel Foundation Grant 10-1488-WI 2 (to E. W.), European Union Grant FIGH-CT-2002-00218 (to E. W. and Prof. George Iliakis), and National Institutes of Health Grant 1R01 HD42558-01 (to E. W. and S. J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables I and II.

To whom correspondence should be addressed. Tel.: 49-201-723-4387; Fax: 49-201-723-5635; E-mail: e.winterhager{at}uni-essen.de.

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