Induction of KLF4 in basal keratinocytes blocks the proliferation - differentiation switch and initiates squamous epithelial dysplasia
Induction of KLF4 in basal keratinocytes blocks the proliferation - differentiation switch and initiates squamous epithelial dysplasia
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DOI：
10.1038/sj.onc.1208307
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发表时间：
2005-02-24
期刊：
影响因子：
8
通讯作者：
Ruppert, JM
中科院分区：
文献类型：
--
作者：
Foster, KW;Liu, ZL;Ruppert, JM
KLF 4/GKLF通常在分化上皮细胞中起作用，但在体外也充当转化癌基因。为了研究这种锌指蛋白在皮肤中的作用，我们从诱导型和组成型启动子表达了野生型人类等位基因。当在基底角质形成细胞中诱导时，KLF 4迅速消除基底和副基底上皮细胞的独特特性。KLF 4引起短暂的凋亡反应，皮肤通过增生和发育不良阶段进展。到6周时，病变表现出核KLF 4和其他形态学和分子相似性鳞状细胞原位癌。p53决定了足以建立损伤的斑片大小，因为只有当p53缺乏时，镶嵌图案中的诱导才产生皮肤损伤。与p53野生型动物相比，p53半合子动物有早期发病的病变和明显的纤维血管反应，包括皮下肉瘤的生长。一种KLF 4-雌激素受体融合蛋白在体外表现出他莫昔芬依赖的核定位和条件转化。结果表明，KLF 4可以在细胞核中发挥作用，诱导鳞状上皮发育不良，并表明p53和上皮间质信号传导在这些早期肿瘤性病变中的作用。
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.