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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

Graham, Nicholas A. and Asthagiri, Anand R. (2004) 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. Journal of Biological Chemistry, 279 (22). pp. 23517-23524. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:GRAjbc04

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Abstract

Because beta-catenin target genes such as cyclin D1 are involved in cell cycle progression, we examined whether beta-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 G(1)/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 G(1)/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.


Item Type:Article
Additional Information:Copyright © 2004 by the American Society for Biochemistry and Molecular Biology. Received for publication, December 23, 2003, and in revised form, March 2, 2004. Published, JBC Papers in Press, March 16, 2004, DOI 10.1074/jbc.M314055200. We thank Joan Brugge for helpful discussions and Eric Fearon, Kenneth Kinzler, and David Schaffer for providing reagents. 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. [N.A.G. was] [s]upported by the National Defense Science and Engineering Graduate fellowship.
Subject Keywords:GLYCOGEN-SYNTHASE KINASE-3; ACTIVATED PROTEIN-KINASE; COLON-CARCINOMA CELLS; BETA-CATENIN PATHWAY; E-CADHERIN; NEOPLASTIC TRANSFORMATION; NUCLEAR TRANSLOCATION; CANCER-CELLS; EXPRESSION; INHIBITION
Record Number:CaltechAUTHORS:GRAjbc04
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:GRAjbc04
Alternative URL:http://dx.doi.org/10.1074/jbc.M314055200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7086
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Jan 2007
Last Modified:26 Dec 2012 09:28

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