期刊
ONCOGENE
卷 24, 期 9, 页码 1491-1500出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208307
关键词
KLF4; squamous cell carcinoma; dysplasia; doxycycline; MMTV
资金
- NCI NIH HHS [P50 CA089019, P30 CA013148, R01 CA094030, R29 CA065686, CA89019, R01 CA065686, CA65686, CA094030, P30CA13148] Funding Source: Medline
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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