真核细胞中G1期到S期的转换是细胞增殖的关键步骤，与发育、再生和肿瘤等密切相关，G1期细胞周期蛋白 (G1 cyclin) 在其中发挥重要的作用。以往我们已经证实G1 cyclin缺失后，胚胎干细胞等可较正常生长，为 “G1 cyclin非依赖型细胞”；而成纤维细胞却停止增殖分化，为 “G1 cyclin 依赖型细胞” 。本项目将在G1 cyclin knockout模型上，通过cyclin A补救G1 cyclin缺失后表型，来了解 G1 cyclin非依赖型和依赖型G1/S期转换机制和其意义；我们将比较这两类细胞的蛋白表达和磷酸化情况，在分子水平阐述 G1 cyclin非依赖型增殖机制，找出可能的新细胞增殖调控因子，研究其在肿瘤中的作用；我们还将建立只靠cyclin B来维持增殖的哺乳动物模型，挑战对细胞周期的传统认识。本项目对认识细胞周期核心机制和肿瘤细胞的异常增殖具有重要的意义。

The accurate transition from G1 phase of the cell cycle to S phase is crucial for the control of eukaryotic cell proliferation, and associated with development, regeneration and cancer. G1 cyclins play critical roles in G1/S transition. In our previous study, some types of cells (such as embryonic stem cells) are G1 cyclin-independent and still can proliferate nearly normally without any G1 cyclin. But fibroblasts are G1 cyclin-dependent. They stop growing completely after ablation of all G1 cyclins. It is very impotent to understand the difference of core cell cycle machinery among different cell types. However, the mechanisms involved still remain unclear. In this study, based on G1 cyclin-knockout model, we will rescue phenotypes caused by G1 cyclin deletion by overexpression of cyclin A, to understand G1/S transition mechanisms in G1 cyclin- independent and -dependent cells. We will also elucidate the molecular basis of G1 cyclin-independent proliferation by analyse and compare the protein profiles and phosphoproteomes in G1 cyclin-independent and -dependent cells, find out the potential proliferation regulated factors, and test their functions in human cancer cell lines. Moreover, we will generate a new model with only cyclin B driving whole cell cycle. This model will challenge our current knowledge about mammalian cell cycle. In summary, this study may uncover new mechanisms of G1 cyclin-independent proliferation and have a significant impact on our understanding of mammalian cell proliferation, including cancer cell proliferation.