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Signaling and Regulation

The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor ß–Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer

¹ Department of Internal Medicine I, University of Ulm, Germany and ² Department of Internal Medicine, Division of Gastroenterology and Endocrinology, University of Marburg, Marburg, Germany

Requests for reprints: Volker Ellenrieder, Innere Medizin, SP Gastroenterologie, Baldingerstraße, 35043 Marburg, Germany. Phone: 49-6421-286-2318; Fax: 49-6421-286-8922. E-mail: ellenrie{at}med.uni-marburg.de

c-myc promoter silencing is a key step in epithelial cell growth inhibition by transforming growth factor ß (TGFß). During carcinogenesis, however, epithelial cells escape from c-myc repression and consequently become refractory to TGFß-mediated antiproliferation. Here, we assessed the role of the repressor, KLF11, in TGFß-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 TGFß-stimulated normal epithelial cells, nuclear KLF11, in concert with Smad3, binds to and represses transcription from the core region of the TGFß-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 TGFß-mediated growth inhibition. In pancreatic cancer cells with oncogenic Ras mutations, hyperactive ERK counteracts TGFß-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 TGFß-induced c-myc repression and antiproliferation and identifies a novel mechanism through which ERK signaling antagonizes the tumor suppressor activities of TGFß in pancreatic cancer cells with oncogenic Ras mutations. (Mol Cancer Res 2006;4(11):861–72)

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