Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach.
OBJECTIVE
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.
Katz
Jonathan P
JP
Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104-6145, USA.
Perreault
Nathalie
N
Goldstein
Bree G
BG
Actman
Lori
L
McNally
Sara R
SR
Silberg
Debra G
DG
Furth
Emma E
EE
Kaestner
Klaus H
KH
D000818:Animals; D000071616:CDX2 Transcription Factor; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005753:Gastric Mucosa / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006706:Homeostasis; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000378:metabolism; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071164:Trefoil Factor-2
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C000604007:TFF2 protein, human; D014157:Transcription Factors; D000071164:Trefoil Factor-2