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

Oncogene volume 24, pages 1491–1500 (2005)Cite this 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 signaling in these early neoplastic lesions.

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Acknowledgements

We thank Andrzej A Dlugosz for advice on keratinocyte isolation, and Lawrence A Donehower for advice on p53 genotyping. This research was supported by Grants CA65686, CA094030, CA89019, and P30CA13148 from the US National Cancer Institute and by a gift to the Comprehensive Cancer Center from the Avon Foundation.

Author information

Author notes

  1. K Wade Foster

    Present address: Department of Dermatology, EFH 414, 1720 University Blvd, Birmingham, AL, 35233, USA

  2. Iuri D Louro

    Present address: Universidade Federal do Espírito Santo, Vitória, ES 29052-620, Brazil

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    K Wade Foster, Tim M Townes & J Michael Ruppert

  2. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Zhaoli Liu, Xingnan Li & J Michael Ruppert

  3. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Clinton D Nail, Thomas J Fitzgerald, Sarah K Bailey, Iuri D Louro, Andrew J Paterson, Jeffrey E Kudlow, Susan M Lobo-Ruppert & J Michael Ruppert

  4. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Andra R Frost

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Correspondence to J Michael Ruppert.

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Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Foster, K., Liu, Z., Nail, C. et al. Induction of KLF4 in basal keratinocytes blocks the proliferation–differentiation switch and initiates squamous epithelial dysplasia. Oncogene 24, 1491–1500 (2005). https://doi.org/10.1038/sj.onc.1208307

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