G1-phase cyclin dependent kinases (Cdks) are required for proliferation and normal development. The activity of these complexes is modulated predominately by growth factors and mitogens which promote proliferation by inducing the expression of G1-phase cyclins. However, the mechanisms that control the timing, expression levels, and activity of G1-phase cyclins are still not well understood. Thus, the broad and long-term goals of my laboratory are to identify and dissect the genetic, molecular and biochemical pathways that control G1-phase cyclin expression and to determine the role of G1-phase Cdks in cell growth control. Using yeast as a genetic model system, we have demonstrated that G1-phase cyclin expression, and importantly, the proliferation rate of cells, is strongly linked to cell size;large cells express G1-phase cyclins sooner and to higher levels as compared to small cells. Subsequently, large cells proliferate much more rapidly than small cells. Because G1-phase Cdks and the basic mechanisms of cell cycle control are so highly conserved, we hypothesize that mammalian cell proliferation and G1-phase cyclin expression are also linked to cell size. Moreover, since hyper-activation of G1-phase Cdks is implicated in the causation of cancer, the demonstration of a mechanistic link between cell size, G1-phase cyclin expression, and proliferation in mammalian cells will be both biologically and clinically relevant. Therefore, in this proposal, we address three questions: 1. Is proliferation rate of mammalian cells linked to cell size?, 2. How is the expression of G1-phase cyclins linked to cell size?, and 3. Does G1-phase Cdk activity link proliferation rate to cell size? Completion of the experiments proposed in this grant will greatly clarify the relationships between cell size, G1-phase Cdk activity, and the proliferative capacity of cells. We propose that linking cell size to proliferation rate using G1-phase Cdks represents an important physiological means that enables large resting cells (e.g. stem cells) to proliferate rapidly in response to stimuli-an important conserved function specific to stem cells. However, the inability to appropriately down regulate G1 -phase Cdk activity might be a cause of cancer. This exemplifies the critical importance of understanding the role of G1-phase Cdks in proliferation because this type of information is essential before effective anti-cancer clinical interventions can be designed.
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