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

Academic Article

Abstract

  • 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 signalling in these early neoplastic lesions. © 2005 Nature Publishing Group All rights reserved.
  • Digital Object Identifier (doi)

    Author List

  • Foster KW; Liu Z; Nail CD; Li X; Fitzgerald TJ; Bailey SK; Frost AR; Louro ID; Townes TM; Paterson AJ
  • Start Page

  • 1491
  • End Page

  • 1500
  • Volume

  • 24
  • Issue

  • 9