Sicinski P, Donaher J L, Geng Y, Parker S B, Gardner H, Park M Y, Robker R L, Richards J S, McGinnis L K, Biggers J D, Eppig J J, Bronson R T, Elledge S J, Weinberg R A
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA.
Nature. 1996 Dec 5;384(6608):470-4. doi: 10.1038/384470a0.
THE D-type cyclins (D1, D2 and D3) are critical governors of the cell-cycle clock apparatus during the G1 phase of the mammalian cell cycle. These three D-type cyclins are expressed in overlapping, apparently redundant fashion in the proliferating tissues. To investigate why mammalian cells need three distinct D-type cyclins, we have generated mice bearing a disrupted cyclin D2 gene by using gene targeting in embryonic stem cells. Cyclin D2-deficient females are sterile owing to the inability of ovarian granulosa cells to proliferate normally in response to follicle-stimulating hormone (FSH), whereas mutant males display hypoplastic testes. In ovarian granulosa cells, cyclin D2 is specifically induced by FSH via a cyclic-AMP-dependent pathway, indicating that expression of the various D-type cyclins is under control of distinct intracellular signalling pathways. The hypoplasia seen in cyclin D2(-/-) ovaries and testes prompted us to examine human cancers deriving from corresponding tissues. We find that some human ovarian and testicular tumours contain high levels of cyclin D2 messenger RNA.
D型细胞周期蛋白（D1、D2和D3）是哺乳动物细胞周期G1期细胞周期时钟机制的关键调控因子。这三种D型细胞周期蛋白在增殖组织中以重叠且明显冗余的方式表达。为了探究哺乳动物细胞为何需要三种不同的D型细胞周期蛋白，我们通过在胚胎干细胞中进行基因靶向操作，培育出了携带细胞周期蛋白D2基因缺失的小鼠。细胞周期蛋白D2缺陷的雌性小鼠不育，原因是卵巢颗粒细胞无法对促卵泡激素（FSH）作出正常增殖反应，而突变雄性小鼠则表现出睾丸发育不全。在卵巢颗粒细胞中，细胞周期蛋白D2由FSH通过环磷酸腺苷依赖性途径特异性诱导产生，这表明各种D型细胞周期蛋白的表达受不同细胞内信号通路的调控。在细胞周期蛋白D2基因敲除小鼠的卵巢和睾丸中观察到的发育不全现象促使我们研究源自相应组织的人类癌症。我们发现一些人类卵巢和睾丸肿瘤中含有高水平的细胞周期蛋白D2信使核糖核酸。
