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首页> 外文期刊>Cell cycle >Combined effect of cyclin D3 expression and abrogation of cyclin D1 prevent mouse skin tumor development
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Combined effect of cyclin D3 expression and abrogation of cyclin D1 prevent mouse skin tumor development

机译：细胞周期蛋白D3表达和细胞周期蛋白D1消除的联合作用预防小鼠皮肤肿瘤的发展

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We have previously demonstrated that ras-mediated skin tumorigenesis depends on signaling pathways that act preferentially through cyclin D1 and D2. Interestingly, the expression of cyclin D3 inhibits skin tumor development, an observation that conflicts with the oncogenic role of D-type cyclins in the mouse epidermis. Here, we show that simultaneous up and downregulation of particular members of the D-type cyclin family is a valuable approach to reduce skin tumorigenesis. We developed the K5D3/cyclin D1 -/- compound mouse, which overexpresses cyclin D3 but lacks expression of cyclin D1 in the skin. Similar to K5D3 transgenic mice, keratinocytes from K5D3/cyclin D1 -/- compound mice show a significant reduction of cyclin D2 levels. Therefore, this model allows us to determine the effect of cyclin D3 expression when combined with reduced or absent expression of the remaining two members of the D-type cyclin family in mouse epidermis. Our data show that induced expression of cyclin D3 compensates for the reduced level of cyclin D1 and D2, resulting in normal keratinocyte proliferation. However, simultaneous ablation of cyclin D1 and downregulation of cyclin D2 via cyclin D3 expression resulted in a robust reduction in ras-mediated skin tumorigenesis. We conclude that modulation of the levels of particular members of the D-type cyclin family could be useful to inhibit tumor development and, in particular, ras-mediated tumorigenesis.
机译：我们以前已经证明，ras介导的皮肤肿瘤发生取决于优先通过细胞周期蛋白D1和D2发挥作用的信号通路。有趣的是，细胞周期蛋白D3的表达抑制了皮肤肿瘤的发展，这一发现与D型细胞周期蛋白在小鼠表皮中的致癌作用相矛盾。在这里，我们表明D型细胞周期蛋白家族的特定成员的同时上调和下调是减少皮肤肿瘤发生的有价值的方法。我们开发了K5D3 / cyclin D1-/-复合小鼠，它过度表达cyclin D3但在皮肤中缺乏cyclin D1的表达。与K5D3转基因小鼠相似，来自K5D3 / cyclin D1-/-复合小鼠的角质形成细胞显示cyclin D2水平显着降低。因此，当与小鼠表皮中D型细胞周期蛋白家族的其余两个成员的表达降低或缺失时，该模型使我们能够确定细胞周期蛋白D3表达的作用。我们的数据表明，细胞周期蛋白D3的诱导表达可以补偿细胞周期蛋白D1和D2的水平降低，从而导致正常的角质形成细胞增殖。但是，同时消融细胞周期蛋白D1和通过细胞周期蛋白D3表达下调细胞周期蛋白D2导致ras介导的皮肤肿瘤发生的明显减少。我们得出的结论是，调节D型细胞周期蛋白家族特定成员的水平可能有助于抑制肿瘤的发展，尤其是抑制ras介导的肿瘤发生。

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