Kozar Katarzyna, Ciemerych Maria A, Rebel Vivienne I, Shigematsu Hirokazu, Zagozdzon Agnieszka, Sicinska Ewa, Geng Yan, Yu Qunyan, Bhattacharya Shoumo, Bronson Roderick T, Akashi Koichi, Sicinski Piotr
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2004 Aug 20;118(4):477-91. doi: 10.1016/j.cell.2004.07.025.
D-type cyclins (cyclins D1, D2, and D3) are regarded as essential links between cell environment and the core cell cycle machinery. We tested the requirement for D-cyclins in mouse development and in proliferation by generating mice lacking all D-cyclins. We found that these cyclin D1(-/-)D2(-/-)D3(-/-) mice develop until mid/late gestation and die due to heart abnormalities combined with a severe anemia. Our analyses revealed that the D-cyclins are critically required for the expansion of hematopoietic stem cells. In contrast, cyclin D-deficient fibroblasts proliferate nearly normally but show increased requirement for mitogenic stimulation in cell cycle re-entry. We found that the proliferation of cyclin D1(-/-)D2(-/-)D3(-/-) cells is resistant to the inhibition by p16(INK4a), but it critically depends on CDK2. Lastly, we found that cells lacking D-cyclins display reduced susceptibility to the oncogenic transformation. Our results reveal the presence of alternative mechanisms that allow cell cycle progression in a cyclin D-independent fashion.
D型细胞周期蛋白（细胞周期蛋白D1、D2和D3）被视为细胞环境与核心细胞周期机制之间的关键纽带。我们通过培育缺乏所有D型细胞周期蛋白的小鼠，来测试D型细胞周期蛋白在小鼠发育和增殖过程中的必要性。我们发现，这些细胞周期蛋白D1（-/-）D2（-/-）D3（-/-）小鼠能够发育至妊娠中后期，最终因心脏异常并伴有严重贫血而死亡。我们的分析表明，D型细胞周期蛋白对于造血干细胞的扩增至关重要。相比之下，缺乏细胞周期蛋白D的成纤维细胞增殖情况基本正常，但在重新进入细胞周期时对有丝分裂原刺激的需求增加。我们发现，细胞周期蛋白D1（-/-）D2（-/-）D3（-/-）细胞的增殖对p16（INK4a）的抑制具有抗性，但它严重依赖于细胞周期蛋白依赖性激酶2（CDK2）。最后，我们发现缺乏D型细胞周期蛋白的细胞对致癌转化的敏感性降低。我们的研究结果揭示了存在以不依赖细胞周期蛋白D的方式允许细胞周期进程的替代机制。
