Three Observations That Have Changed Our Understanding of Cyclin D1 and p27 in Cell Cycle Control.

Our understanding of cell cycle control has been based largely upon studies of synchronized cultures, often focused upon the early stages of the cell cycle following stimulation of quiescent cultures. These studies showed that cyclin D1 and p27(Kip1) (p27) each respond to the growth environment of the cell and together control entry into the cell cycle. In contrast, all cell cycle phases were considered in these studies of actively growing cultures, including events leading to withdrawal from the cell cycle. This approach relies upon the techniques of microinjection, quantitative image analysis, and time-lapse microscopy. The results provide critical new detail to our understanding of the roles of cyclin D1 and p27 in cell cycle regulation. Three critical observations resulting from this work will be described here to demonstrate that 1) cyclin D1 levels oscillate through the normal cell cycle, 2) checkpoint kinases are able to suppress cyclin D1 during S phase, and 3) the level of p27 is determined by a dynamic interaction between cyclin D1 and p27 so as to determine the rate of cell cycle progression. Based upon these observations, a model of cell cycle control is presented in which ras activity stimulates cyclin D1 during G2 phase, resulting in commitment of the cell to continued cell cycle progression. During G1 phase, ras activity suppresses the level of p27 protein, most of which is bound to cyclin D1, resulting in regulation of the rate of proliferation. This model predicted the involvement of checkpoint kinases in regulating cyclin D1 and the role of checkpoint kinases in the protection of neural cells against reactive oxygen. The substantiation of these 2 predictions serves as general validation of the model.