CyclinAggregation - Molecular Biology of the Cell Vol. 14,...

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Molecular Biology of the Cell Vol. 14, 4695–4706, November 2003 Cyclin Aggregation and Robustness of Bio-switching Boris M. Slepchenko* and Mark Terasaki Center for Biomedical Imaging Technology, Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06032 Submitted April 21, 2003; Revised June 29, 2003; Accepted July 3, 2003 Monitoring Editor: Mark Solomon During the cell cycle, Cdc2-cyclin B kinase abruptly becomes active and triggers the entry into mitosis/meiosis. Recently, it was found that inactive Cdc2-cyclin B is present in aggregates in immature starFsh oocytes and becomes disaggregated at the time of its activation during maturation. We discuss a possible scenario in which aggregation of Cdc2-cyclin B dramatically enhances robustness of this activation. In this scenario, only inactive Cdc2-cyclin B can form aggregates, and the aggregates are in equilibrium with inactive Cdc2-cyclin B in solution. During maturation, the hormone-triggered inactivation of Myt1 depletes the soluble inactive Cdc2-cyclin B and the turnover leads to dissolution of the aggregates. This phase change, when coupled with the instability of the signaling network, provides a robust bio-switch. INTRODUCTION Cells enter M phase decisively and irreversibly. At the mo- lecular level, the decisive event for entry into M phase is the activation of Cdc2 kinase (also known as cyclin-dependent kinase 1) (Nurse, 1990; Murray and Hunt, 1993). Cdc2 has an obligatory requirement for cyclin B binding (Cdc2-cyclin B is also known as M phase promoting factor or MPF). Cdc2- cyclin B activity is regulated by the activating phosphatase Cdc25 and the inactivating Wee1 family kinases, which act on two key phosphorylation sites (Solomon, 1993; Figure 1). In cells, Cdc2 activation is initiated either by changing the balance in favor of Cdc25 over Wee1 or by increasing the total Cdc2-cyclin B. The ±rst way is thought to be more common. The second method has been demonstrated in experimental situations where exogenous cyclin B is added and binds to endogenous Cdc2, which is in excess (Swenson et al ., 1986; Murray and Kirschner, 1989); it may also occur during rapid early embryonic divisions. A crucial feature of the Cdc2 activation pathway is that active Cdc2-cyclin B activates its activator Cdc25 and inactivates its inactivator Wee1 (Figure 1). This positive feedback is thought to result in all or none activation that does not ²icker on and off once it is turned on. Theoretically, the irreversible character of Cdc2 activation can be described in terms of bistability (Tyson et al ., 2001). The fact that cells can be arrested in the inactive state and when activated remain in the active state even after the stimulus is removed implies that the system can be in at least two different stable states separated by some kind of a “barrier.” Recently, experimental evidence for bistable be- havior in Xenopus laevis egg extracts has been reported (Pomerening et al ., 2003; Sha et al ., 2003). This type of behav- ior can be elegantly explained by the possible bistability of a
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This note was uploaded on 09/06/2008 for the course BIOMEDE 418 taught by Professor Hunt during the Winter '08 term at University of Michigan.

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CyclinAggregation - Molecular Biology of the Cell Vol. 14,...

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