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Molecular and Cellular Biology, March 2004, p. 2546-2559, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2546-2559.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor ß-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

Joshua P. Frederick,1 Nicole T. Liberati,1,{dagger} David S. Waddell,1 Yigong Shi,2 and Xiao-Fan Wang1*

Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710,1 Department of Molecular Biology, Princeton University, Princeton, New Jersey 085442

Received 10 April 2003/ Returned for modification 20 May 2003/ Accepted 19 December 2003

Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor ß (TGF-ß) signal. The ability of the Smads to act as transcriptional activators via TGF-ß-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-ß target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-ß-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-ß, and this repression is required for the manifestation of the TGF-ß cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-ß-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-ß inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, P.O. Box 3813, Durham, NC 27710. Phone: (919) 681-4861. Fax: (919) 681-7152. E-mail: wang0011{at}mc.duke.edu.

{dagger} Present address: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.

Molecular and Cellular Biology, March 2004, p. 2546-2559, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2546-2559.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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