Carcinogenesis Advance Access originally published online on May 19, 2006
Carcinogenesis 2006 27(12):2392-2401; doi:10.1093/carcin/bgl078
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Smad–Sp1 complexes mediate TGFß-induced early transcription of oncogenic Smad7 in pancreatic cancer cells
Department of Gastroenterology, University of Ulm 89081 Ulm, Germany
*To whom correspondence should be addressed at: Department of Internal Medicine, University of Ulm, Robert-Koch Strasse 8, 89081 Ulm, Germany. Tel: +49 731 500 24312; Email: volker.ellenrieder{at}medizin.uni-ulm.de
The transcription factor Sp1 has been implicated in cell-type-specific activation of transforming growth factor-ß (TGFß) target genes in normal epithelial cells as well as in aberrant gene activation by TGFß in epithelial tumor cells. Here, we have examined the interaction of Sp1 with components of the Smad signaling cascade and its role in TGFß-induced early gene expression in pancreatic cancer cells. Gene expression profiling was carried out in mithramycin-A-treated cells to identify Sp1-regulated TGFß early response genes. We found that in pancreatic cancer cells Smad proteins and Sp1 cooperatively regulate expression of a distinct set of TGFß target genes potentially involved in tumor progression, including MMP-11, cyclin D1 and Smad7. Mechanistically, TGFß 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 siRNA prevents TGFß-induced Smad7 expression and consequently enhances Smad signaling 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 TGFß stimulation.
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