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Smad-Sp1 complexes mediate TGFbeta-induced early transcription of oncogenic Smad7 in pancreatic cancer cells.
Carcinogenesis. 2006 Dec; 27(12):2392-401.C

Abstract

The transcription factor Sp1 has been implicated in cell-type-specific activation of transforming growth factor-beta (TGFbeta) target genes in normal epithelial cells as well as in aberrant gene activation by TGFbeta in epithelial tumor cells. Here, we have examined the interaction of Sp1 with components of the Smad signaling cascade and its role in TGFbeta-induced early gene expression in pancreatic cancer cells. Gene expression profiling was carried out in mithramycin-A-treated cells to identify Sp1-regulated TGFbeta early response genes. We found that in pancreatic cancer cells Smad proteins and Sp1 cooperatively regulate expression of a distinct set of TGFbeta target genes potentially involved in tumor progression, including MMP-11, cyclin D1 and Smad7. Mechanistically, TGFbeta 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 TGFbeta-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 TGFbeta stimulation.

Authors+Show Affiliations

Department of Gastroenterology, University of Ulm, 89081 Ulm, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16714330

Citation

Jungert, Kerstin, et al. "Smad-Sp1 Complexes Mediate TGFbeta-induced Early Transcription of Oncogenic Smad7 in Pancreatic Cancer Cells." Carcinogenesis, vol. 27, no. 12, 2006, pp. 2392-401.
Jungert K, Buck A, Buchholz M, et al. Smad-Sp1 complexes mediate TGFbeta-induced early transcription of oncogenic Smad7 in pancreatic cancer cells. Carcinogenesis. 2006;27(12):2392-401.
Jungert, K., Buck, A., Buchholz, M., Wagner, M., Adler, G., Gress, T. M., & Ellenrieder, V. (2006). Smad-Sp1 complexes mediate TGFbeta-induced early transcription of oncogenic Smad7 in pancreatic cancer cells. Carcinogenesis, 27(12), 2392-401.
Jungert K, et al. Smad-Sp1 Complexes Mediate TGFbeta-induced Early Transcription of Oncogenic Smad7 in Pancreatic Cancer Cells. Carcinogenesis. 2006;27(12):2392-401. PubMed PMID: 16714330.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Smad-Sp1 complexes mediate TGFbeta-induced early transcription of oncogenic Smad7 in pancreatic cancer cells. AU - Jungert,Kerstin, AU - Buck,Anita, AU - Buchholz,Malte, AU - Wagner,Martin, AU - Adler,Guido, AU - Gress,Thomas M, AU - Ellenrieder,Volker, Y1 - 2006/05/19/ PY - 2006/5/23/pubmed PY - 2007/1/24/medline PY - 2006/5/23/entrez SP - 2392 EP - 401 JF - Carcinogenesis JO - Carcinogenesis VL - 27 IS - 12 N2 - The transcription factor Sp1 has been implicated in cell-type-specific activation of transforming growth factor-beta (TGFbeta) target genes in normal epithelial cells as well as in aberrant gene activation by TGFbeta in epithelial tumor cells. Here, we have examined the interaction of Sp1 with components of the Smad signaling cascade and its role in TGFbeta-induced early gene expression in pancreatic cancer cells. Gene expression profiling was carried out in mithramycin-A-treated cells to identify Sp1-regulated TGFbeta early response genes. We found that in pancreatic cancer cells Smad proteins and Sp1 cooperatively regulate expression of a distinct set of TGFbeta target genes potentially involved in tumor progression, including MMP-11, cyclin D1 and Smad7. Mechanistically, TGFbeta 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 TGFbeta-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 TGFbeta stimulation. SN - 0143-3334 UR - https://www.unboundmedicine.com/medline/citation/16714330/Smad_Sp1_complexes_mediate_TGFbeta_induced_early_transcription_of_oncogenic_Smad7_in_pancreatic_cancer_cells_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgl078 DB - PRIME DP - Unbound Medicine ER -