Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach

Gastroenterology. 2005 Apr;128(4):935-45. doi: 10.1053/j.gastro.2005.02.022.

Abstract

Background & aims: The epithelial zinc-finger transcription factor Klf4 (formerly GKLF) regulates cellular proliferation and differentiation in vitro. Klf4 null mice die by postnatal day 1 and show changes in epithelial differentiation of skin and colon.

Methods: We used tissue-specific gene ablation to generate mice lacking Klf4 in their gastric epithelia. Klf4 mutant mice and controls were killed for histology, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), and serum gastrin levels. Klf4 messenger RNA (mRNA) levels were analyzed in Foxa3-Cdx2 transgenic mice and controls. Human gastric cancers and matched normal tissue were used for qPCR and immunohistochemistry for KLF4.

Results: Klf4 mutant mice survive to adulthood and show increased proliferation and altered differentiation of their gastric epithelia. Klf4 mutants also display aberrant expression of acidic mucins and TFF2/SP-positive cells, findings characteristic of premalignant conditions, but no inflammation, intestinal metaplasia, dysplasia, or cancer up to 1 year of age. Expression of KLF4 is nearly absent in human gastric cancer, suggesting that failure to activate KLF4 during normal cellular differentiation may be a common feature of gastric cancers. p21 WAF1/CIP1 is an in vivo target of Klf4, but Klf4 is not a mediator of Cdx2.

Conclusions: Loss of a single genetic factor, Klf4, leads to dramatic changes in the gastric epithelia of mice, and Klf4 is part of a regulatory pathway involving p21 WAF1/CIP1 but not Cdx2. Thus, Klf4 is critical for normal gastric epithelial homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CDX2 Transcription Factor
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gastric Mucosa / pathology
  • Homeodomain Proteins / metabolism
  • Homeostasis
  • Kruppel-Like Transcription Factors
  • Mice
  • Mutation*
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology*
  • Stomach / pathology*
  • Stomach Neoplasms / metabolism
  • Tissue Distribution
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Trefoil Factor-2

Substances

  • CDX2 Transcription Factor
  • CDX2 protein, human
  • Cdkn1a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • GKLF protein
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • TFF2 protein, human
  • Transcription Factors
  • Trefoil Factor-2