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J. Biol. Chem., Vol. 279, Issue 35, 36943-36950, August 27, 2004

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CCN3 (NOV) Interacts with Connexin43 in C6 Glioma Cells

POSSIBLE MECHANISM OF CONNEXIN-MEDIATED GROWTH SUPPRESSION^*

Christine T. Fu, John F. Bechberger, Mark A. Ozog, Bernard Perbal, and Christian C. Naus¶

From the Department of Anatomy and Cell Biology, University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada and Laboratoire d'Oncologie Virale et Moleculaire, UFR de Biochimie, Universite Paris 7-D Diderot, Paris 75005, France

Many tumor cells exhibit aberrant gap junctional intercellular communication, which can be restored by transfection with connexin genes. We have previously discovered that overexpression of connexin43 (Cx43) in C6 glioma cells not only reduces proliferation but also leads to production of soluble growth-inhibitory factors. We identified that several members of the CCN (Cyr61/connective tissue growth factor/nephroblastoma-overexpressed) family are up-regulated following Cx43 expression, including CCN3 (NOV). We now report evidence for an association between CCN3 and Cx43. Western blot analysis demonstrated that the 48-kDa full-length CCN3 protein was present in the lysate and conditioned medium of growth-suppressed C6-Cx43 cells, as well as primary astrocytes, but not in C6 parental and human glioma cells. Immunocytochemical examination of CCN3 revealed diffuse localization in parental C6 cells, whereas transfection of C6 cells with Cx43 (C6-Cx43) or with a modified Cx43 tagged to green fluorescent protein on its C terminus (Cx43-GFP) resulted in punctate staining, suggesting that CCN3 co-localizes with Cx43 in plaques at the plasma membrane. In cells expressing a C-terminal truncation of Cx43 (Cx43244-382), this co-localization was lost. Glutathione S-transferase pull-down assay and co-immunoprecipitation demonstrated that CCN3 was able to physically interact with Cx43. In contrast, CCN3 was not found to associate with Cx43244-382. Similar experiments revealed that CCN3 did not co-localize or associate with other connexins, including Cx40 or Cx32. Taken together, these data support an interaction of CCN3 with the C terminus of Cx43, which could play an important role in mediating growth control induced by specific gap junction proteins.

Received for publication, April 9, 2004 , and in revised form, June 15, 2004.

^* This research was supported by grants from the Canadian Institutes of Health Research (to C. C. N.) and from the Ligue Nationale contre le Cancer (Comité du Cher) (to B. P.). 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.

^¶ To whom correspondence may be addressed. E-mail: christian.naus{at}ubc.ca.

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