Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid.
Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid.
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DOI：
10.4161/cbt.8.3.7486
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发表时间：
2009-02
影响因子：
3.6
通讯作者：
Lobo-Ruppert SM
中科院分区：
文献类型：
--
作者：
Jiang W;Deng W;Bailey SK;Nail CD;Frost AR;Brouillette WJ;Muccio DD;Grubbs CJ;Ruppert JM;Lobo-Ruppert SM
转录因子KLF 4在有丝分裂后的上皮细胞中起作用以促进分化，并以环境依赖的方式作为癌基因发挥作用。在皮肤中，KLF 4与核受体RARγ和RXRα共表达，皮肤渗透屏障的形成是这三种蛋白质的共同功能。我们利用KLF 4转基因小鼠皮肤癌模型与培养的上皮细胞相结合，研究KLF 4和维甲酸受体之间的功能相互作用。在培养的细胞中，4-羟基他莫昔芬激活条件性KLF 4-雌激素受体融合蛋白，导致核受体（包括RARγ和RXRα）的转录物快速上调。我们在上皮细胞转化试验中测试了类维生素A，包括RAR选择性激动剂（全反式RA），RXR选择性激动剂（9-顺式UAB 30，rexinoid）和泛激动剂（9-顺式RA）。与其他几个基因不同，KLF 4的转化被每个类维生素A抑制，暗示不同的核受体异二聚体作为KLF 4转化活性的调节剂。当RNAi抑制培养细胞中RXRα的表达时，转化被促进，9-cis UAB 30的抑制作用被减弱。与其他皮肤癌小鼠模型相似，rexinoid阻止了由基底角质形成细胞中KLF 4诱导引起的皮肤肿瘤发生。Rexinoid允许KLF 4表达和KLF 4诱导的细胞周期，但减弱KLF 4诱导的基底细胞中细胞角蛋白1的错误表达。包括增生、异型增生和鳞状细胞癌样病变在内的肿瘤病变可预防长达30天。综上所述，结果确定了包括RXRα在内的类维生素A受体作为KLF 4介导的转化或肿瘤发生的配体依赖性抑制剂。
The transcription factor KLF4 acts in post-mitotic epithelial cells to promote differentiation, and functions in a context-dependent fashion as an oncogene. In the skin KLF4 is co-expressed with the nuclear receptors RARγ and RXRα, and formation of the skin permeability barrier is a shared function of these three proteins. We utilized a KLF4-transgenic mouse model of skin cancer in combination with cultured epithelial cells to examine functional interactions between KLF4 and retinoic acid receptors. In cultured cells, activation of a conditional, KLF4-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in rapid upregulation of transcripts for nuclear receptors including RARγ and RXRα. We tested retinoids in epithelial cell transformation assays, including an RAR-selective agonist (all-trans RA), an RXR-selective agonist (9-cis UAB30, rexinoid), and a pan agonist (9-cis RA). Unlike for several other genes, transformation by KLF4 was inhibited by each retinoid, implicating distinct nuclear receptor heterodimers as modulators of KLF4 transforming activity. When RXRα expression was suppressed by RNAi in cultured cells, transformation was promoted and the inhibitory effect of 9-cis UAB30 was attenuated. Similarly as shown for other mouse models of skin cancer, rexinoid prevented skin tumor initiation resulting from induction of KLF4 in basal keratinocytes. Rexinoid permitted KLF4 expression and KLF4-induced cell cycling, but attenuated the KLF4-induced misexpression of cytokeratin 1 in basal cells. Neoplastic lesions including hyperplasia, dysplasia and squamous cell carcinoma-like lesions were prevented for up to 30 days. Taken together, the results identify retinoid receptors including RXRα as ligand-dependent inhibitors of KLF4-mediated transformation or tumorigenesis.
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影响因子：
7.8
作者：
Frisch, S M
通讯作者：
Frisch, S M
影响因子：
64.8
作者：
Li, M;Indra, AK;Chambon, P
通讯作者：
Chambon, P
影响因子：
8
作者：
Foster, KW;Liu, ZL;Ruppert, JM
通讯作者：
Ruppert, JM
影响因子：
14.9
作者：
LITTLEWOOD, TD;HANCOCK, DC;EVEN, GI
通讯作者：
EVEN, GI
影响因子：
7.3
作者：
Atigadda, VR;Vines, KK;Muccio, DD
通讯作者：
Muccio, DD