Control of mitotic transitions by the anaphase-promoting complex

Proteolysis controls key transitions at several points in the cell cycle. I n mitosis, the activation of a large ubiquitin-protein ligase, the anaphase -promoting complex (APC), is required for anaphase initiation and for exit from mitosis. We show that APC is under complex control by a network of reg ulatory factors, CDC20, CDH1 and MAD2. CDC20 and CDH1 are activators of APC ; they bind directly to APC and activate its cyclin ubiquitination activity . CDC20 activates APC at the onset of anaphase in a destruction box (DB)-de pendent manner, while CDH1 activates APC from late anaphase through G1 with apparently a much relaxed specificity for the DB. Therefore, CDC20 and CDH 1 control both the temporal order of activation and the substrate specifici ty of APC, and hence regulate different events during mitosis and G1. Count eracting the effect of CDC20, the checkpoint protein MAD2 acts as an inhibi tor of APC. When the spindle-assembly checkpoint is activated, MAD2 forms a ternary complex with CDC20 and APC to prevent activation of APC, and there by arrests cells at prometaphase. Thus, a combination of positive and negat ive regulators establishes a regulatory circuit of APC, ensuring an ordered progression of events through cell division.