ABSTRACT

T he duplication and division of cells occurs through a precisely regulated series of morphological and mechanistic steps. This process, termed the cell-division cycle, is controlled by a complex regulatory program. Destruction of regulatory proteins via ubiquitin-dependent proteasomal path­ ways is a major and essential mechanistic step in various aspects of cell cycle control. Proteolysis as a regulatory tool of the cell cycle was first suggested by the discovery of cyclin proteins whose levels oscillate as cells progress through the phases of the cell cycle. Cyclins bind and activate cyclin-dependent kinases (CDKs) that are central regulators of the cell cycle (for a recent review see ref. 1). Inactivation of mitotic CDKs by proteolytic destruction of B-type cyclins was the first cell-cycle regulatory event shown to be mediated by a ubiquitin-dependent proteasomal pathway.2 The subsequent discovery of other unstable cell cycle regulators showed that regulatory proteolysis via the proteasome acts at many levels of cell-cycle control. Proteolytic destruction is required to remove proteins that function as CDK inhibitors, thereby leading to activation of CDK complexes. Proteasomal degradation also controls the quantity of other proteins that are not directly linked to CDK function, but rather act as regulators of other cell-cycle processes or as structural elements of the cell-cycle machinery.