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

Gastroenterology. 2004 Aug;127(2):607-20. doi: 10.1053/j.gastro.2004.05.018.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • CHO Cells
  • COS Cells
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / physiopathology
  • Cell Cycle Proteins*
  • Cricetinae
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • GC Rich Sequence
  • Gene Expression Regulation, Neoplastic
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / pharmacology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / physiopathology
  • Phosphorylation
  • Promoter Regions, Genetic
  • Repressor Proteins / metabolism
  • Sin3 Histone Deacetylase and Corepressor Complex
  • Smad2 Protein
  • Smad7 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism*
  • Transcription Factors / pharmacology
  • Transcription, Genetic / physiology
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • ras Proteins / metabolism


  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • KLF11 protein, human
  • Nuclear Proteins
  • Repressor Proteins
  • SIN3A transcription factor
  • Smad2 Protein
  • Smad7 Protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Mitogen-Activated Protein Kinases
  • Sin3 Histone Deacetylase and Corepressor Complex
  • ras Proteins