Switches and latches : the control of entry into Mitosis

Orateur : Dr Tim HUNT (Cancer Research UK, London Research institute, Clare Hall Laboratories, Herts, UK)

The process of mitosis involves a comprehensive reorganization of the cell : chromosomes condense, the nuclear envelope breaks down, the mitotic spindle is assembled, cells round up and release their ties to the substrate and so on and so forth. This reorganization is triggered by the activation of the protein kinase, Cyclin-Dependent Kinase 1 (CDK1). The end of mitosis is marked by the proteolysis of the B-type cyclin subunit of CDK1, which terminates kinase activity. At this point, the phosphate moieties that altered the properties of hundreds of proteins to bring about the reorganization of the cell are removed by protein phosphatases. We recently began to pay attention to the control of these enzymes, considering it likely that they were shut off as cells enter mitosis, and reactivated when mitosis is complete, to allow the return to interphase. We discovered that at least one protein phosphatase, PP2A-B55, is shut off in mitosis. Depletion of this particular form of PP2A accelerates entry into mitosis, and blocks exit from mitosis. Control of this phosphatase is achieved by an inhibitor protein (a-endosulfine or ARPP-19) that becomes a powerful and specific inhibitor of PP2A-B55 when phosphorylated by a protein kinase called Greatwall, which is itself a substrate of, and activated by, CDK1 (and, maybe, is a substrate of PP2A). Failure to inhibit PP2A-B55 causes arrest of the cell cycle in G2 phase. I will discuss the role of this control mechanism in the control of mitosis. We still have a rather incomplete understanding of exactly how the timing of entry into mitosis is controlled.

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