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J. Biol. Chem., Vol. 278, Issue 44, 43846-43854, October 31, 2003

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Opposing Roles of C/EBP and AP-1 in the Control of Fibroblast Proliferation and Growth Arrest-specific Gene Expression^*

Mark Gagliardi, Scott Maynard¶, Tetsuaki Miyake, Natalie Rodrigues||, Sie Lung Tjew, Eric Cabannes**, and Pierre-André Bédard

From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada and the Department of Biology, McMaster University, Hamilton, Ontario L8S 1K4, Canada

Chicken embryo fibroblasts (CEF) express several growth arrest-specific (GAS) gene products in G₀. In contact-inhibited cells, the expression of the most abundant of these proteins, the p20K lipocalin, is activated at the transcriptional level by C/EBP. In this report, we describe the role of C/EBP in CEF proliferation. We show that the expression of a dominant negative mutant of C/EBP (designated 184-C/EBP) completely inhibited p20K expression at confluence and stimulated the proliferation of CEF without inducing transformation. Mouse embryo fibroblasts nullizygous for C/EBP had a proliferative advantage over cells with one or two functional copies of this gene. C/EBP inhibition enhanced the expression of the three major components of AP-1 in cycling CEF, namely c-Jun, JunD, and Fra-2, and stimulated AP-1 activity. In contrast, the over-expression of C/EBP caused a dramatic reduction in the levels of AP-1 proteins. Therefore, C/EBP is a negative regulator of AP-1 expression and activity in CEF. The expression of cyclin D1 and cell proliferation were stimulated by the dominant negative mutant of C/EBP but not in the presence of TAM67, a dominant negative mutant of c-Jun and AP-1. CEF over-expressing c-Jun, and to a lesser extent JunD and Fra-2, did not growth arrest at high cell density and did not express p20K. Therefore, AP-1 interfered with the action of C/EBP at high cell density, indicating that these factors play opposing roles in the control of GAS gene expression and CEF proliferation.

Received for publication, April 18, 2003 , and in revised form, July 25, 2003.

^* This work was made possible by grants from the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research (to P.-A. B.). 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.

Present address: Samuel Lunenfeld Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

^¶ Present address: Cancer Center and Gerontology Center, University of Michigan, Ann Harbor, MI 48109.

^|| Present address: Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.

^** Present address: Institut Pasteur, Unité d'Immunologie Virale, Bât. SIDA-Rétrovirus, 28 rue du Dr Roux, 75724 Paris, Cedex 15, France.

To whom correspondence should be addressed. Tel.: 905-525-9140 (ext. 23149); Fax: 905-522-6066; E-mail: abedard{at}mcmaster.ca.

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