Welcker M, Lukas J, Strauss M, Bartek J
Danish Cancer Society, Division of Cancer Biology, Copenhagen, Denmark.
Oncogene. 1996 Jul 18;13(2):419-25.
The mammalian D-type cyclins promote progression through a G1 checkpoint by phosphorylating the retinoblastoma protein (pRB), and can contribute to oncogenesis via their deregulated expression achieved through gene amplification, chromosomal rearrangement, or retroviral integration. We now report a novel mechanism of tumour-associated D-cyclin over-abundance, resulting from enhanced protein stability. In two human cell lines established from a single uterine sarcoma biopsy, pRB-positive SK-UT-1B and pRB-deficient SK-UT-1, aberrant accumulation of functional cyclins D1, and D2 and D3 occurred in the absence of gene amplification and/or elevated mRNA expression. The abundance of D-cyclin proteins remained elevated throughout the cell cycle, and pulse-chase experiments revealed six to 10-fold prolongation of their protein half-lives as compared with either diploid fibroblasts or control U-2-OS sarcoma cells. These results point to a critical regulatory role of D-type cyclin turnover, and contribute to refinement of current views of the role played by the cyclin D-CDK-p16-pRB pathway in cell cycle control and tumorigenesis.
哺乳动物的D型细胞周期蛋白通过磷酸化视网膜母细胞瘤蛋白（pRB）促进细胞通过G1检查点，并且可通过基因扩增、染色体重排或逆转录病毒整合导致的表达失调而促进肿瘤发生。我们现在报告一种由蛋白质稳定性增强导致的肿瘤相关D型细胞周期蛋白过度表达的新机制。在从单次子宫肉瘤活检建立的两个人类细胞系中，pRB阳性的SK-UT-1B和pRB缺陷的SK-UT-1，功能性细胞周期蛋白D1、D2和D3在没有基因扩增和/或mRNA表达升高的情况下发生异常积累。D型细胞周期蛋白的丰度在整个细胞周期中保持升高，脉冲追踪实验显示与二倍体成纤维细胞或对照U-2-OS肉瘤细胞相比，其蛋白质半衰期延长了6至10倍。这些结果表明D型细胞周期蛋白周转具有关键的调节作用，并有助于完善目前关于细胞周期蛋白D-CDK-p16-pRB途径在细胞周期控制和肿瘤发生中所起作用的观点。
