KLF11 mediates a critical mechanism in TGF-β signaling that is inactivated by ERK-MAPK in pancreatic cancer cells

Volker Ellenrieder, Anita Buck, Ana Harth, Kerstin Jungert, Malte Buchholz, Guido Adler, Raul Urrutia, Thomas M. Gress

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Background & Aims: Smad-regulated transcription plays a central role in transforming growth factor (TGF)-β-induced cell growth inhibition and tumor suppression. Like the Smads, KLF11 is an early response transcription factor that mediates TGF-β-induced growth inhibition in untransformed epithelial cells. Here, we investigated the functional implications of KLF11 in TGF-β signaling and transcription in normal epithelial as well as pancreatic cancer cells. Methods: The effects of KLF11 on TGF-β signaling and transcription were examined on the levels of reporter transactivation, Smad2 phosphorylation, and expression of endogenous TGF-β-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-β signaling by terminating the inhibitory Smad7 loop. Mechanistically, KLF11 represses TGF-β-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-β signaling in pancreatic cancer cells. Conclusions: These results define a novel mechanism in TGF-β-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.

Original languageEnglish (US)
Pages (from-to)607-620
Number of pages14
Issue number2
StatePublished - Aug 2004


  • GST
  • MAPK
  • PCR
  • SBE
  • SID
  • Sin3a-HDAC interacting domain
  • Smad-binding element
  • TGF
  • glutathione S-transferase
  • mitogen-activated protein kinase
  • polymerase chain reaction
  • transforming growth factor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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