Induction of KLF4 in Basal Keratinocytes Blocks the Proliferation-differentiation Switch and Initiates Squamous Epithelial Dysplasia

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2005 Jan 28

PMID 15674344

Citations 106

Authors

K Wade Foster

Zhaoli Liu

Clinton D Nail

Xingnan Li

Thomas J Fitzgerald

Sarah K Bailey

Andra R Frost

Iuri D Louro

Tim M Townes

Andrew J Paterson

Jeffrey E Kudlow

Susan M Lobo-Ruppert

J Michael Ruppert

Affiliations

Soon will be listed here.

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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