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J. Biol. Chem., Vol. 279, Issue 22, 23759-23765, May 28, 2004

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Opposite Smad and Chicken Ovalbumin Upstream Promoter Transcription Factor Inputs in the Regulation of the Collagen VII Gene Promoter by Transforming Growth Factor-^*

María Julia Calonge, Joan Seoane, and Joan Massagué

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

A critical component of the epidermal basement membrane, collagen type VII, is produced by keratinocytes and fibroblasts, and its production is stimulated by the cytokine transforming growth factor- (TGF-). The gene, COL7A1, is activated by TGF- via Smad transcription factors in cooperation with AP1. Here we report a previously unsuspected level of complexity in this regulatory process. We provide evidence that TGF- may activate the COL7A1 promoter by two distinct inputs operating through a common region of the promoter. One input is provided by TGF--induced Smad complexes via two Smad binding elements that function redundantly depending on the cell type. The second input is provided by relieving the COL7A1 promoter from chicken ovalbumin upstream promoter transcription factor (COUP-TF)-mediated transcriptional repression. We identified COUP-TFI and -TFII as factors that bind to the TGF--responsive region of the COL7A1 promoter in an expression library screening. COUP-TFs bind to a site between the two Smad binding elements independently of Smad or AP1 and repress the basal and TGF--stimulated activities of this promoter. We provide evidence that endogenous COUP-TF activity represses the COL7A1 promoter. Furthermore, we show that TGF- addition causes a rapid and profound down-regulation of COUP-TF expression in keratinocytes and fibroblasts. The results suggest that TGF- signaling may exert tight control over COL7A1 by offsetting the balance between opposing Smad and COUP-TFs.

Received for publication, February 27, 2004

^* This work was supported by a National Institutes of Health Cancer Center grant to Memorial Sloan-Kettering Cancer Center and by National Institutes of Health Grant CA34610 (to J. M.). 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.

Present address: ICREA, Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute, Barcelona, Spain.

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

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