Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.
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.
Foster
K Wade
KW
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Liu
Zhaoli
Z
Nail
Clinton D
CD
Li
Xingnan
X
Fitzgerald
Thomas J
TJ
Bailey
Sarah K
SK
Frost
Andra R
AR
Louro
Iuri D
ID
Townes
Tim M
TM
Paterson
Andrew J
AJ
Kudlow
Jeffrey E
JE
Lobo-Ruppert
Susan M
SM
Ruppert
J Michael
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects*; D003433:Crosses, Genetic; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004317:Doxorubicin / Q000494:pharmacology; D004847:Epithelial Cells / Q000473:pathology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012867:Skin / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection
D017931:DNA Primers; D004268:DNA-Binding Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D004317:Doxorubicin