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Originally published In Press as doi:10.1074/jbc.M301413200 on June 24, 2003

J. Biol. Chem., Vol. 278, Issue 37, 35444-35450, September 12, 2003
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Mad Upregulation and Id2 Repression Accompany Transforming Growth Factor (TGF)-{beta}-mediated Epithelial Cell Growth Suppression*

Peter M. Siegel {ddagger}, Weiping Shu and Joan Massagué §

From the Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The growth inhibitory cytokine TGF-{beta} enforces homeostasis of epithelia by activating processes such as cell cycle arrest and apoptosis. Id2 expression is often highest in proliferating epithelial cells and declines during differentiation. Recently, Id2 expression has been found to depend on Myc-Max transcriptional complexes. We observed that TGF-{beta} signaling inhibits Id2 expression in human and mouse epithelial cell lines from different tissue origins. Furthermore, the observed Id2 down-regulation by TGF-{beta} in mouse mammary epithelial cells occurs without a concurrent drop in c-Myc levels. However, sustained Id2 repression in these cells and in human keratinocytes coincides with induction of the Myc antagonistic repressors Mad2 and Mad4, decreased formation of Myc-Max heterodimers and the replacement of Myc-Max complexes with Mad-Max complexes on the Id2 promoter. These results argue that induction of Mad expression and Id2 down-regulation are important events during the TGF-{beta} cytostatic program in epithelial cells.


Received for publication, February 10, 2003 , and in revised form, June 23, 2003.

* This work was supported by National Institutes of Health Grant CA94060 (to J. M.) and to Memorial Sloan-Kettering Cancer Center. 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.

{ddagger} Supported by a fellowship from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation (DRG-1532).

§ An Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Cell Biology Program, Box 116, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Tel.: 212-639-8975; Fax: 212-717-3298; E-mail: j-massague{at}ski.mskcc.org.


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