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Molecular and Cellular Biology, September 2003, p. 6646-6661, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6646-6661.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

GATA- and Smad1-Dependent Enhancers in the Smad7 Gene Differentially Interpret Bone Morphogenetic Protein Concentrations

Hassina Benchabane and Jeffrey L. Wrana*

Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada

Received 30 April 2003/ Returned for modification 11 June 2003/ Accepted 16 June 2003

Smad7, an inhibitor of transforming growth factor beta superfamily signaling, is induced by bone morphogenetic protein (BMP) in an inhibitory feedback loop. Here, we identify multiple BMP response elements (BREs) in the Smad7 gene and demonstrate that they function differentially to interpret BMP signals in a cell type-specific manner. Two BREs (BRE-1 and -2) reside in the promoter region. One of these contains several conserved Smad1 and Smad4 binding sites that cooperate to mediate BMP-dependent induction, most likely in the absence of DNA binding partners. The third BRE (I-BRE) resides in the first intron and contains GATA factor binding sites. GATA-1, -5, or -6 is required for strong activation of I-BRE, and we show that they assemble with Smad1 on the I-BRE in living cells. Activation of the I-BRE is mediated by a specific region in GATA-5 and -6 but does not require direct physical interaction with Smad1. Comparison of I-BRE to BRE-1 showed that I-BRE is more responsive to low BMP concentrations. Moreover, analysis by chromatin immunoprecipitation experiments demonstrates that the endogenous I-BRE is occupied more robustly by endogenous Smad1 than is BRE-1. This correlates with regulation of the Smad7 gene, which is induced at lower BMP concentrations in GATA-expressing cell lines compared to non-GATA-expressing lines. These data thus define how cooperative and noncooperative Smad-dependent transcriptional regulation can function to interpret different BMP concentrations.

* Corresponding author. Mailing address: Rm. 1075, SLRI, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Phone: (416) 586-4800, ext. 2791. Fax: (416) 586-8869. E-mail: wrana{at}mshri.on.ca.

Molecular and Cellular Biology, September 2003, p. 6646-6661, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6646-6661.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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