The role of controlled proteolysis in cell-cycle regulation.

Abstract

Cyclins and cyclin-dependent kinases are key regulators of the cell cycle. The binding of different cyclins, required to activate the catalytically inactive cyclin-dependent kinases, determines the substrate specificity of the enzymes. Cyclin-dependent-kinase inhibitors have an adverse effect, blocking the catalytic activity of cyclin-activated cyclin-dependent kinases. The cell cycle is a cyclic process of successive transient activation or inactivation of cyclin-dependent kinases by association with different cyclin regulatory subunits or cyclin-dependent kinase inhibitors. As the concentration of cyclin-dependent kinases is fairly constant during the cell cycle and exceeds the total amount of cyclins present in the cell, the exchange of regulatory subunits is determined by the availability of the different cyclins. Transcriptional control of cyclin gene expression is the most decisive factor determining the total amount of different cyclins synthesized. The actual concentration of a cyclin, however, is always the result of an equilibrium between the rates of its synthesis and degradation. While cyclin gene expression has long been known to be cell-cycle controlled, the idea of the rapid destruction of cyclins or cyclin-dependent-kinase inhibitors as an equally important factor contributing to the progress of the cell cycle is more recent. The role of controlled proteolysis in the regulation of cell cycle is discussed in this review. Two general features of this regulation are worth mentioning: cyclin-dependent kinases activated by different cyclin regulatory subunits have a central role both in the transcriptional regulation of their own genes and in the regulated, selective destruction of cyclins or cyclin-dependent kinase inhibitors; transcriptional regulation of cyclin gene expression ensures fine-tuned, continuous changes, and controlled proteolysis generates abrupt, irreversible transitions. The progress of the cell cycle is based on a delicate balance of the these mutual, but opposite regulations.