Unexpected reduction of skin tumorigenesis on expression of cyclin-dependent kinase 6 in mouse epidermis.
Unexpected reduction of skin tumorigenesis on expression of cyclin-dependent kinase 6 in mouse epidermis.
复制标题
小鼠表皮中细胞周期蛋白依赖性激酶 6 的表达意外地减少了皮肤肿瘤的发生。
DOI：
10.1016/j.ajpath.2010.11.032
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Rodriguez-Puebla,MarceloL
中科院分区：
文献类型：
--
作者：
Wang,Xian;Sistrunk,Christopher;Rodriguez-Puebla,MarceloL
细胞周期蛋白依赖性激酶（CDK）4和6是细胞周期G1期的重要调节因子，共有71%的氨基酸同源性，并且广泛表达。因此，假设这些激酶中的每一种都在调节正常和肿瘤增殖中起着多余的作用。在以前的报告中，我们已经描述了CDK 4表达在转基因小鼠中的作用，包括表皮增生的发展和鳞状细胞癌恶性进展的增加。为了研究CDK 6在上皮生长和肿瘤发生中的作用，我们产生了在角蛋白5启动子（K5 CDK 6）下携带CDK 6基因的转基因小鼠。与K5 CDK 4小鼠相似，K5 CDK 6小鼠的表皮增殖显著增加;然而，未观察到增生。CDK 6过表达还触发了毛囊间和毛囊表皮中的角质形成细胞凋亡，作为覆盖异常增殖的补偿机制。出乎意料的是，与野生型同胞相比，CDK 6过表达导致皮肤肿瘤发展减少。对皮肤肿瘤发生的抑制作用与先前在K5-细胞周期蛋白D3小鼠中报道的相似。此外，K5 CDK 6表皮的生化分析显示CDK 6和细胞周期蛋白D3之间的优先复合物形成，这表明这种特殊的复合物在肿瘤抑制中起着重要作用。这些研究提供了体内证据表明，CDK 4和CDK 6作为角质形成细胞增殖的介质发挥相似的作用，但在凋亡活化和皮肤肿瘤发展方面不同。
Cyclin-dependent kinases (CDKs) 4 and 6 are important regulators of the G1phase of the cell cycle, share 71% amino acid identity, and are expressed ubiquitously. As a result, it was assumed that each of these kinases plays a redundant role regulating normal and neoplastic proliferation. In previous reports, we have described the effects of CDK4 expression in transgenic mice, including the development of epidermal hyperplasia and increased malignant progression to squamous cell carcinoma. To study the role of CDK6 in epithelial growth and tumorigenesis, we generated transgenic mice carrying the CDK6 gene under the keratin 5 promoter (K5CDK6). Similar to K5CDK4 mice, epidermal proliferation increased substantially in K5CDK6 mice; however, no hyperplasia was observed. CDK6 overexpression also triggered keratinocyte apoptosis in interfollicular and follicular epidermis as a compensatory mechanism to override aberrant proliferation. Unexpectedly, CDK6 overexpression results in decreased skin tumor development compared with wild-type siblings. The inhibition in skin tumorigenesis was similar to that previously reported in K5-cyclin D3 mice. Furthermore, biochemical analysis of the K5CDK6 epidermis showed preferential complex formation between CDK6 and cyclin D3, suggesting that this particular complex plays an important role in tumor restraint. These studies provide in vivo evidence that CDK4 and CDK6 play a similar role as a mediator of keratinocyte proliferation but differ in apoptosis activation and skin tumor development.