Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion
Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion
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DOI：
10.1073/pnas.96.17.9827
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发表时间：
1999-08-17
影响因子：
11.1
通讯作者：
Colburn, N
中科院分区：
文献类型：
--
作者：
Young, MR;Li, JJ;Colburn, N
激活蛋白-1（AP-1）是由Jun-Jun同源二聚体或Jun-Fos异源二聚体组成的转录因子，AP-1的反式激活是肿瘤启动子诱导的小鼠表皮JB 6细胞转化以及小鼠和人角质形成细胞进展所必需的。如具有功能重要性的靶基因的问题。为了解决这些问题，我们已经产生了一个转基因小鼠，其中反式激活突变体c-jun（TAM 67），在人角蛋白-14启动子的控制下，特异性地表达在肿瘤诱导开始的表皮基底细胞。角蛋白-14-TAM 67转基因在表皮、舌和宫颈中表达，在任何组织或器官中没有明显异常，TAM 67表达阻断了12-O-十四酰佛波醇13-乙酸酯。（TPA，佛波醇12-十四烷酸酯13-乙酸酯）诱导AP-1荧光素酶/TAM 67小鼠中AP-1调节的荧光素酶，但不抑制候选AP-1靶基因的诱导，更有趣的是，TAM 67表达不抑制TPA诱导的过度增殖。在两个阶段的皮肤癌发生实验中，转基因动物表现出显着抑制乳头状瘤的诱导。我们得出结论，AP-1依赖性基因的子集的反式激活是肿瘤促进所必需的，并且可以被靶向用于癌症预防。
Activator protein-1 (AP-1) is a transcription factor that consists of either a Jun-Jun homodimer or a Jun-Fos heterodimer, Transactivation of AP-1 is required for tumor promoter-induced transformation in mouse epidermal JB6 cells and for progression in mouse and human keratinocytes, Until now, the question of whether AP-1 transactivation is required for carcinogenesis in vivo has remained unanswered, as has the issue of functionally significant target genes. To address these issues we have generated a transgenic mouse in which transactivation mutant c-jun (TAM67), under the control of the human keratin-14 promoter, is expressed specifically in the basal cells of the epidermis where tumor induction is initiated. The keratin-14-TAM67 transgene was expressed in the epidermis, tongue, and cervix, with no apparent abnormalities in any tissue or organ, TAM67 expression blocked 12-O-tetradecanoylphorbol 13-acetate (TPA, phorbol 12-tetradecanoate 13-acetate) induction of the AP-1-regulated luciferase in AP-1 luciferase/TAM67 mice, but did not inhibit induction of candidate AP-1 target genes, collagenase-1 or stromelysin-3, More interestingly, TAM67 expression did not inhibit TPA-induced hyperproliferation. In two-stage skin carcinogenesis experiments, the transgenic animals showed a dramatic inhibition of papilloma induction. We conclude that transactivation of a subset of AP-l-dependent genes is required for tumor promotion and may be targeted for cancer prevention.