Mouse development and cell proliferation in the absence of D-cyclins
Mouse development and cell proliferation in the absence of D-cyclins
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DOI：
10.1016/j.cell.2004.07.025
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发表时间：
2004-08-20
期刊：
影响因子：
64.5
通讯作者：
Sicinski, P
中科院分区：
文献类型：
--
作者：
Kozar, K;Ciemerych, MA;Sicinski, P
D型细胞周期蛋白（细胞周期蛋白D1，D2和D3）被认为是细胞环境和核心细胞周期机制之间的重要联系。我们通过产生缺乏所有D-细胞周期蛋白的小鼠来测试小鼠发育和增殖中对D-细胞周期蛋白的需求。我们发现，这些细胞周期蛋白D1（-/-）D2（-/-）D3（-/-）小鼠发育至妊娠中期/晚期，并因心脏异常和严重贫血而死亡。我们的分析表明，D-cyclin是造血干细胞扩增所必需的。与此相反，细胞周期蛋白D缺陷的成纤维细胞增殖几乎正常，但在细胞周期重新进入有丝分裂刺激的需求增加。我们发现cyclin D1（-/-）D2（-/-）D3（-/-）细胞的增殖对p16（INK 4a）的抑制有抵抗作用，但对CDK 2有重要的依赖性。最后，我们发现缺乏D-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替代机制的存在，使细胞周期的进展在一个周期蛋白D-independent的方式。
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-cyclin; 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-indeperdent fashion.