Selective role for Mek1 but not Mek2 in the induction of epidermal neoplasia.
Selective role for Mek1 but not Mek2 in the induction of epidermal neoplasia.
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DOI：
10.1158/0008-5472.can-08-1963
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Khavari PA
中科院分区：
文献类型：
--
作者：
Scholl FA;Dumesic PA;Barragan DI;Harada K;Charron J;Khavari PA
Ras/Raf/Mek/Erk丝裂原活化蛋白激酶途径调节正常和恶性细胞中的基本过程，包括增殖、分化和细胞存活。该途径中的突变与致癌和发育障碍有关，使Mek 1和Mek 2成为主要的治疗靶点。在这项研究中，我们使用两步7，12-二甲基苯并蒽/12-O-十四烷酰基佛波醇-13-乙酸酯（DMBA/TPA）皮肤致癌模型研究了皮肤肿瘤形成对Mek 1和Mek 2的需求。DMBA/TPA治疗后，缺乏表皮Mek 1蛋白的小鼠比野生型和Mek 2缺失小鼠发生乳头状瘤的数量少。Mek 1基因敲除小鼠的乳头状瘤较小，肿瘤发病延迟，肿瘤负荷为野生型小鼠的一半。然而，一个Mek 1等位基因的丢失并不影响肿瘤的发展，这表明一个Mek 1等位基因足以形成正常的乳头状瘤。TPA诱导的过度增殖，炎症，或Erk激活之间没有观察到野生型，条件性Mek 1敲除，和Mek 2-null小鼠的差异，表明Mek 1的发现是不是由于这些过程的一般故障。这些数据表明，Mek 1是重要的皮肤肿瘤的发展和Mek 2不能弥补Mek 1功能的损失，在这种情况下。
The Ras/Raf/Mek/Erk mitogen-activated protein kinase pathway regulates fundamental processes in normal and malignant cells, including proliferation, differentiation, and cell survival. Mutations in this pathway have been associated with carcinogenesis and developmental disorders, making Mek1 and Mek2 prime therapeutic targets. In this study, we examined the requirement for Mek1 and Mek2 in skin neoplasia using the two-step 7,12-dimethylbenz(a)anthraacene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) skin carcinogenesis model. Mice lacking epidermal Mek1 protein develop fewer papillomas than both wild-type and Mek2-null mice following DMBA/TPA treatment. Mek1 knockout mice had smaller papillomas, delayed tumor onset, and half the tumor burden of wild-type mice. Loss of one Mek1 allele, however, did not affect tumor development, indicating that one Mek1 allele is sufficient for normal papilloma formation. No difference in TPA-induced hyperproliferation, inflammation, or Erk activation was observed between wild-type, conditional Mek1 knockout, and Mek2-null mice, indicating that Mek1 findings were not due to a general failure of these processes. These data show that Mek1 is important for skin tumor development and that Mek2 cannot compensate for the loss of Mek1 function in this setting.