Dual role of inactivating Lef1 mutations in epidermis: Tumor promotion and specification of tumor type
Dual role of inactivating Lef1 mutations in epidermis: Tumor promotion and specification of tumor type
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DOI：
10.1158/0008-5472.can-06-3427
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Watt, Fiona M.
中科院分区：
文献类型：
--
作者：
Niemann, Catherin;Owens, David M.;Watt, Fiona M.
LEF 1的NH 2末端在人皮脂腺肿瘤中经常发生突变。为了研究这是如何导致癌症的，我们对K14 Delta NLeft转基因小鼠进行了两阶段化学致癌作用，这些小鼠在表皮基底层中表达NH 2末端截短的Left。即使没有暴露于肿瘤促进剂，转基因小鼠也比同窝对照小鼠更快地发展出更多的肿瘤。他们发展成皮脂腺肿瘤，而对照组发展成鳞状细胞癌。K14 AN左表皮在肿瘤发生过程中或对UV照射的反应中未能上调p53和p21蛋白，这与p14 ARF诱导受损相关。我们认为LEF 1 NH 2-末端突变在皮肤癌中起着双重作用，通过抑制Wnt信号传导来指定肿瘤类型，并通过阻止p53的诱导来作为肿瘤促进剂。
The NH2 terminus of LEF1 is frequently mutated in human sebaceous tumors. To investigate how this contributes to cancer, we did two-stage chemical carcinogenesis on K14 Delta NLeft transgenic mice, which express NH2-terminally truncated Left in the epidermal basal layer. Transgenic mice developed more tumors, more rapidly than littermate controls, even without exposure to tumor promoter. They developed sebaccous tumors, whereas controls developed squamous cell carcinomas. K14ANLeft epidermis failed to up-regulate p53 and p21 proteins during tumorigenesis or in response to UV irradiation, and this correlated with impaired p14ARF induction. We propose that LEF1 NH2-terminal mutations play a dual role in skin cancer, specifying tumor type by inhibiting Wnt signaling and acting as a tumor promoter by preventing induction of p53.