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.
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-Cdx2transgenic mice and controls. Humangastric 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 humangastric 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.
Authors: Chen-Chung Lin; Ling-Zhi Liu; Joseph B Addison; William F Wonderlin; Alexey V Ivanov; J Michael Ruppert Journal: Mol Cell Biol Date: 2011-04-25 Impact factor: 4.272
Authors: Victoria G Weis; Josane F Sousa; Bonnie J LaFleur; Ki Taek Nam; Jared A Weis; Paul E Finke; Nadia A Ameen; James G Fox; James R Goldenring Journal: Gut Date: 2012-07-07 Impact factor: 23.059
Authors: Rita Vassena; Zhiming Han; Shaorong Gao; Donald A Baldwin; Richard M Schultz; Keith E Latham Journal: Dev Biol Date: 2006-12-12 Impact factor: 3.582
Authors: Mark W Feinberg; Akm Khyrul Wara; Zhuoxiao Cao; Maria A Lebedeva; Frank Rosenbauer; Hiromi Iwasaki; Hideyo Hirai; Jonathan P Katz; Richard L Haspel; Susan Gray; Koichi Akashi; Julie Segre; Klaus H Kaestner; Daniel G Tenen; Mukesh K Jain Journal: EMBO J Date: 2007-08-30 Impact factor: 11.598