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J. Biol. Chem., Vol. 279, Issue 22, 23517-23524, May 28, 2004

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Epidermal Growth Factor-mediated T-cell Factor/Lymphoid Enhancer Factor Transcriptional Activity Is Essential but Not Sufficient for Cell Cycle Progression in Nontransformed Mammary Epithelial Cells^*

Nicholas A. Graham and Anand R. Asthagiri

From the Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

Because -catenin target genes such as cyclin D1 are involved in cell cycle progression, we examined whether -catenin has a more pervasive role in normal cell proliferation, even upon stimulation by non-Wnt ligands. Here, we demonstrate that epidermal growth factor (EGF) stimulates T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcriptional activity in nontransformed mammary epithelial cells (MCF-10A) and that its transcriptional activity is essential for EGF-mediated progression through G₁/S phase. Thus, expression of dominant-negative Tcf4 blocks EGF-mediated Tcf/Lef transcriptional activity and bromodeoxyuridine uptake. In fact, the importance of EGF-mediated Tcf/Lef transcriptional activity for cell cycle progression may lie further upstream at the G₁/S phase transition. We demonstrate that dominant-negative Tcf4 inhibits a reporter of cyclin D1 promoter activity in a dose-dependent manner. Importantly, dominant-negative Tcf4 suppresses EGF-mediated cell cycle activity specifically by thwarting EGF-mediated Tcf/Lef transcriptional activity, not by broader effects on EGF signaling. Thus, although expression of dominant-negative Tcf4 blocks EGF-mediated TOPFLASH activation, it has no effect on either EGF receptor or ERK phosphorylation, further underscoring the fact that Tcf/Lef-mediated transcription is essential for cell cycle progression, even when other pro-mitogenic signals are at normal levels. Yet, despite its essential role, Tcf/Lef transcriptional activity alone is not sufficient for cell cycle progression. Serum also stimulates Tcf/Lef transcriptional activation in MCF-10A cells but is unable to promote DNA synthesis. Taken together, our data support a model wherein EGF promotes Tcf/Lef transcriptional activity, and this signal is essential but not sufficient for cell cycle activity.

Received for publication, December 23, 2003 , and in revised form, March 2, 2004.

^* This work was supported by California Institute of Technology. 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.

Supported by the National Defense Science and Engineering Graduate fellowship.

To whom correspondence should be addressed: Mail Code 210-41, California Institute of Technology, Pasadena, CA 91125. Tel.: 626-395-8130; Fax: 626-568-8743; E-mail: anand{at}cheme.caltech.edu.

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