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The tumor suppressor KLF11 mediates a novel mechanism in transforming growth factor beta-induced growth inhibition that is inactivated in pancreatic cancer.
Mol Cancer Res. 2006 Nov; 4(11):861-72.MC

Abstract

c-myc promoter silencing is a key step in epithelial cell growth inhibition by transforming growth factor beta (TGFbeta). During carcinogenesis, however, epithelial cells escape from c-myc repression and consequently become refractory to TGFbeta-mediated antiproliferation. Here, we assessed the role of the repressor, KLF11, in TGFbeta-induced growth inhibition in normal epithelial as well as pancreatic carcinoma cells. Endogenous KLF11 was stably down-regulated by RNA interference technology, and the functional consequences were studied by proliferation assays, reporter assays, DNA binding studies, and expression analyses. Coimmunoprecipitation and glutathione S-transferase pulldown assays were conducted to define KLF11-Smad3 interaction and U0126 was administered to examine the effects of the extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase on complex formation and c-myc promoter binding of KLF11 and Smad3 in pancreatic cancer cells. In TGFbeta-stimulated normal epithelial cells, nuclear KLF11, in concert with Smad3, binds to and represses transcription from the core region of the TGFbeta-inhibitory element (TIE) of the c-myc promoter. Disruption of KLF11-Smad3 interaction or small interfering RNA-mediated knockdown of endogenous KLF11 strongly diminishes Smad3-TIE promoter binding and repression, and consequently impairs TGFbeta-mediated growth inhibition. In pancreatic cancer cells with oncogenic Ras mutations, hyperactive ERK counteracts TGFbeta-induced c-myc repression and growth inhibition through at least two mechanisms, i.e., via disruption of KLF11-Smad3 complex formation and through inhibition of KLF11-Smad3 binding to the TIE element. Together, these results suggest a central role for KLF11 in TGFbeta-induced c-myc repression and antiproliferation and identifies a novel mechanism through which ERK signaling antagonizes the tumor suppressor activities of TGFbeta in pancreatic cancer cells with oncogenic Ras mutations.

Authors+Show Affiliations

Department of Internal Medicine I, University of Ulm, Germany.No 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

17114344

Citation

Buck, Anita, et al. "The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor Beta-induced Growth Inhibition That Is Inactivated in Pancreatic Cancer." Molecular Cancer Research : MCR, vol. 4, no. 11, 2006, pp. 861-72.
Buck A, Buchholz M, Wagner M, et al. The tumor suppressor KLF11 mediates a novel mechanism in transforming growth factor beta-induced growth inhibition that is inactivated in pancreatic cancer. Mol Cancer Res. 2006;4(11):861-72.
Buck, A., Buchholz, M., Wagner, M., Adler, G., Gress, T., & Ellenrieder, V. (2006). The tumor suppressor KLF11 mediates a novel mechanism in transforming growth factor beta-induced growth inhibition that is inactivated in pancreatic cancer. Molecular Cancer Research : MCR, 4(11), 861-72.
Buck A, et al. The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor Beta-induced Growth Inhibition That Is Inactivated in Pancreatic Cancer. Mol Cancer Res. 2006;4(11):861-72. PubMed PMID: 17114344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The tumor suppressor KLF11 mediates a novel mechanism in transforming growth factor beta-induced growth inhibition that is inactivated in pancreatic cancer. AU - Buck,Anita, AU - Buchholz,Malte, AU - Wagner,Martin, AU - Adler,Guido, AU - Gress,Thomas, AU - Ellenrieder,Volker, PY - 2006/11/23/pubmed PY - 2007/1/11/medline PY - 2006/11/23/entrez SP - 861 EP - 72 JF - Molecular cancer research : MCR JO - Mol Cancer Res VL - 4 IS - 11 N2 - c-myc promoter silencing is a key step in epithelial cell growth inhibition by transforming growth factor beta (TGFbeta). During carcinogenesis, however, epithelial cells escape from c-myc repression and consequently become refractory to TGFbeta-mediated antiproliferation. Here, we assessed the role of the repressor, KLF11, in TGFbeta-induced growth inhibition in normal epithelial as well as pancreatic carcinoma cells. Endogenous KLF11 was stably down-regulated by RNA interference technology, and the functional consequences were studied by proliferation assays, reporter assays, DNA binding studies, and expression analyses. Coimmunoprecipitation and glutathione S-transferase pulldown assays were conducted to define KLF11-Smad3 interaction and U0126 was administered to examine the effects of the extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase on complex formation and c-myc promoter binding of KLF11 and Smad3 in pancreatic cancer cells. In TGFbeta-stimulated normal epithelial cells, nuclear KLF11, in concert with Smad3, binds to and represses transcription from the core region of the TGFbeta-inhibitory element (TIE) of the c-myc promoter. Disruption of KLF11-Smad3 interaction or small interfering RNA-mediated knockdown of endogenous KLF11 strongly diminishes Smad3-TIE promoter binding and repression, and consequently impairs TGFbeta-mediated growth inhibition. In pancreatic cancer cells with oncogenic Ras mutations, hyperactive ERK counteracts TGFbeta-induced c-myc repression and growth inhibition through at least two mechanisms, i.e., via disruption of KLF11-Smad3 complex formation and through inhibition of KLF11-Smad3 binding to the TIE element. Together, these results suggest a central role for KLF11 in TGFbeta-induced c-myc repression and antiproliferation and identifies a novel mechanism through which ERK signaling antagonizes the tumor suppressor activities of TGFbeta in pancreatic cancer cells with oncogenic Ras mutations. SN - 1541-7786 UR - https://www.unboundmedicine.com/medline/citation/17114344/The_tumor_suppressor_KLF11_mediates_a_novel_mechanism_in_transforming_growth_factor_beta_induced_growth_inhibition_that_is_inactivated_in_pancreatic_cancer_ L2 - http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17114344 DB - PRIME DP - Unbound Medicine ER -