BACKGROUND & AIMS: Smad-regulated transcription plays a central role in transforming growth factor (TGF)-beta-induced cell growth inhibition and tumor suppression. Like the Smads, KLF11 is an early response transcription factor that mediates TGF-beta-induced growth inhibition in untransformed epithelial cells. Here, we investigated the functional implications of KLF11 in TGF-beta signaling and transcription in normal epithelial as well as pancreatic cancer cells. METHODS: The effects of KLF11 on TGF-beta signaling and transcription were examined on the levels of reporter transactivation, Smad2 phosphorylation, and expression of endogenous TGF-beta-regulated genes. Promoter analysis, real-time polymerase chain reaction, and coimmunoprecipitation studies were performed to study KLF11-induced and mSin3A corepressor-mediated repression of Smad7. Erk-induced KLF11 phosphorylation was examined in vitro and in vivo, and its impact on KLF11-mSin3A-mediated Smad7 repression was verified in pancreatic cancer cells using site-directed mutagenesis. RESULTS: KLF11 potentiates TGF-beta signaling by terminating the inhibitory Smad7 loop. Mechanistically, KLF11 represses TGF-beta-induced transcription from the Smad7 promoter by recruiting mSin3a via GC-rich sites. This function is inhibited in pancreatic cancer cells with oncogenic Ras mutations, in which Erk/mitogen-activated protein kinase phosphorylates KLF11, leading to disruption of KLF11-mSin3a interaction. Expression of an Erk-insensitive KLF11 mutant restores both mSin3a binding and Smad7 repression and results in enhanced TGF-beta signaling in pancreatic cancer cells. CONCLUSIONS: These results define a novel mechanism in TGF-beta-regulated gene expression. KLF11 potentiates Smad-signaling activity in normal epithelial cells through termination of the negative feedback loop imposed by Smad7. The fact that this function of KLF11 is inhibited by oncogenic Erk/mitogen-activated protein kinase in pancreatic cancer cells emphasizes the importance of this mechanism for oncogenesis.
BACKGROUND & AIMS: Smad-regulated transcription plays a central role in transforming growth factor (TGF)-beta-induced cell growth inhibition and tumor suppression. Like the Smads, KLF11 is an early response transcription factor that mediates TGF-beta-induced growth inhibition in untransformed epithelial cells. Here, we investigated the functional implications of KLF11 in TGF-beta signaling and transcription in normal epithelial as well as pancreatic cancer cells. METHODS: The effects of KLF11 on TGF-beta signaling and transcription were examined on the levels of reporter transactivation, Smad2 phosphorylation, and expression of endogenous TGF-beta-regulated genes. Promoter analysis, real-time polymerase chain reaction, and coimmunoprecipitation studies were performed to study KLF11-induced and mSin3A corepressor-mediated repression of Smad7. Erk-induced KLF11 phosphorylation was examined in vitro and in vivo, and its impact on KLF11-mSin3A-mediated Smad7 repression was verified in pancreatic cancer cells using site-directed mutagenesis. RESULTS:KLF11 potentiates TGF-beta signaling by terminating the inhibitory Smad7 loop. Mechanistically, KLF11 represses TGF-beta-induced transcription from the Smad7 promoter by recruiting mSin3a via GC-rich sites. This function is inhibited in pancreatic cancer cells with oncogenic Ras mutations, in which Erk/mitogen-activated protein kinase phosphorylates KLF11, leading to disruption of KLF11-mSin3a interaction. Expression of an Erk-insensitive KLF11 mutant restores both mSin3a binding and Smad7 repression and results in enhanced TGF-beta signaling in pancreatic cancer cells. CONCLUSIONS: These results define a novel mechanism in TGF-beta-regulated gene expression. KLF11 potentiates Smad-signaling activity in normal epithelial cells through termination of the negative feedback loop imposed by Smad7. The fact that this function of KLF11 is inhibited by oncogenic Erk/mitogen-activated protein kinase in pancreatic cancer cells emphasizes the importance of this mechanism for oncogenesis.
Authors: Malte Buchholz; Alexandra Schatz; Martin Wagner; Patrick Michl; Thomas Linhart; Guido Adler; Thomas M Gress; Volker Ellenrieder Journal: EMBO J Date: 2006-07-27 Impact factor: 11.598
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