Niemann Catherin, Owens David M, Schettina Peter, Watt Fiona M
Cancer Research UK London Research Institute, London, United Kingdom.
Cancer Res. 2007 Apr 1;67(7):2916-21. doi: 10.1158/0008-5472.CAN-06-3427.
The NH(2) terminus of LEF1 is frequently mutated in human sebaceous tumors. To investigate how this contributes to cancer, we did two-stage chemical carcinogenesis on K14DeltaNLef1 transgenic mice, which express NH(2)-terminally truncated Lef1 in the epidermal basal layer. Transgenic mice developed more tumors, more rapidly than littermate controls, even without exposure to tumor promoter. They developed sebaceous tumors, whereas controls developed squamous cell carcinomas. K14DeltaNLef1 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 NH(2)-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.
LEF1的氨基末端在人类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，我们在K14DeltaNLef1转基因小鼠上进行了两阶段化学致癌实验，这些小鼠在表皮基底层表达氨基末端截短的Lef1。转基因小鼠比同窝对照更快地长出更多肿瘤，即使没有接触肿瘤启动子。它们长出了皮脂腺肿瘤，而对照长出了鳞状细胞癌。K14DeltaNLef1表皮在肿瘤发生过程中或对紫外线照射的反应中未能上调p53和p21蛋白，这与p14ARF诱导受损相关。我们提出，LEF1氨基末端突变在皮肤癌中起双重作用，通过抑制Wnt信号指定肿瘤类型，并通过阻止p53的诱导作为肿瘤启动子。
