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Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.

Oncogene | Feb 24, 2005

KLF4/GKLF normally functions in differentiating epithelial cells, but also acts as a transforming oncogene in vitro. To examine the role of this zinc finger protein in skin, we expressed the wild-type human allele from inducible and constitutive promoters. When induced in basal keratinocytes, KLF4 rapidly abolished the distinctive properties of basal and parabasal epithelial cells. KLF4 caused a transitory apoptotic response and the skin progressed through phases of hyperplasia and dysplasia. By 6 weeks, lesions exhibited nuclear KLF4 and other morphologic and molecular similarities to squamous cell carcinoma in situ. p53 determined the patch size sufficient to establish lesions, as induction in a mosaic pattern produced skin lesions only when p53 was deficient. Compared with p53 wild-type animals, p53 hemizygous animals had early onset of lesions and a pronounced fibrovascular response that included outgrowth of subcutaneous sarcoma. A KLF4-estrogen receptor fusion protein showed tamoxifen-dependent nuclear localization and conditional transformation in vitro. The results suggest that KLF4 can function in the nucleus to induce squamous epithelial dysplasia, and indicate roles for p53 and epithelial-mesenchymal signaling in these early neoplastic lesions.

Pubmed ID: 15674344 RIS Download

Mesh terms: Animals | Apoptosis | Cell Differentiation | Cell Division | Crosses, Genetic | DNA Primers | DNA-Binding Proteins | Doxorubicin | Epithelial Cells | Humans | Keratinocytes | Kruppel-Like Transcription Factors | Male | Mice | Mice, Inbred C57BL | Polymerase Chain Reaction | Skin | Transcription Factors | Transfection

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Associated grants

  • Agency: NCI NIH HHS, Id: P30CA13148
  • Agency: NCI NIH HHS, Id: P50 CA089019
  • Agency: NCI NIH HHS, Id: P30 CA013148
  • Agency: NCI NIH HHS, Id: R01 CA094030
  • Agency: NCI NIH HHS, Id: R29 CA065686
  • Agency: NCI NIH HHS, Id: CA89019
  • Agency: NCI NIH HHS, Id: R01 CA065686
  • Agency: NCI NIH HHS, Id: CA65686
  • Agency: NCI NIH HHS, Id: CA094030

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