Carcinogenesis Advance Access published online on May 19, 2006
Carcinogenesis, doi:10.1093/carcin/bgl078
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1 Department of Gastroenterology, University of Ulm, 89081 Ulm, Germany
* To whom correspondence should be addressed. The transcription factor Sp1 has been implicated in cell type-specific activation of transforming growth factor
Received October 19, 2005
Revised April 27, 2006
Accepted May 10, 2006
CANCER BIOLOGY
Smad-Sp1 complexes mediate TGF
Kerstin Jungert 1 *,
Anita Buck 1 *,
Malte Buchholz 1,
Martin Wagner 1,
Guido Adler 1,
Thomas M. Gress 1,
and
Volker Ellenrieder 1 *
-induced early transcription of oncogenic Smad7 in pancreatic cancer cells
Volker Ellenrieder, E-mail: volker.ellenrieder{at}medizin.uni-ulm.de
Abstract 
(TGF) target genes in normal epithelial cells as well as in aberrant gene activation by TGF in epithelial tumor cells. Here, we have examined the interaction of Sp1 with components of the Smad signaling cascade and its role in TGF-induced early gene expression in pancreatic cancer cells. Gene expression profiling was carried out in mithramycin A treated cells to identify Sp1-regulated TGF-early response genes. We found, that in pancreatic cancer cells, Smad proteins and Sp1 cooperatively regulate expression of a distinct set of TGF target genes potentially involved in tumor progression, including MMP-11, cyclin D1 and Smad7. Mechanistically, TGF rapidly induces nuclear translocation of Smad proteins and subsequently stimulates Smad/Sp1 complex formation. Using the Smad7 promoter as a model for Smad/Sp1-induced early gene activation, we demonstrated that this interaction increases Sp1-binding to GC-rich promoter boxes and results in superinduction of Sp1-mediated transcription. Moreover, inhibition of Sp1-DNA binding or transfection of Sp1-specific RNAi prevents TGF-induced Smad7 expression and consequently enhances Smad signalling in pancreatic cancer cells, as indicated by increased receptor-mediated phosphorylation of Smad3. We thus conclude that Sp1 strongly contributes to the aberrant transcriptional response of transformed epithelial cells to TGF stimulation.; transcription; Sp1; Smad7.
*K. J. and A. B. contributed equally to this work
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