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Title page for ETD etd-04152005-100234


Type of Document Dissertation
Author Wolfe, Benjamin
Author's Email Address ben.wolfe@vanderbilt.edu
URN etd-04152005-100234
Title Regulation of mitotic exit in S. pombe through activation of a Cdc14 family phosphatase
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
David Greenstein Committee Chair
Brian Wadzinski Committee Member
Chris Hardy Committee Member
Jennifer Pietenpol Committee Member
Kathleen Gould Committee Member
Keywords
  • phosphatase
  • fission yeast
  • cell cycle
Date of Defense 2005-04-01
Availability unrestricted
Abstract
Progression through the eukaryotic cell cycle involves the coordinated activation and inactivation of cyclin dependent kinases. One such family member, Cdk1p in a complex with Cyclin B, is activated at the G2/M transition in all eukaryotes and initiates the chain of events that ultimately lead to the phenotypic changes that occur during the progression through mitosis. The inactivation of Cdk1p-cyclin B at mitotic exit must be coordinated with respect to chromosome segregation to link nuclear and cytoplasmic divisions. This inactivation not only involves irreversible destruction of Cyclin B, but also a reversal of Cdk1p dependent phosphorylation events by the conserved Cdc14 family of protein phosphatases. We have identified the Cdc14 family member, Clp1p, in the fission yeast Schizosaccharomyces pombe, and studied how the disruption of Cdk1p phosphorylation events influences the coordinated inactivation of mitotic Cdk1p activity. Clp1p specifically disrupts the Cdk1p self-sustaining amplification loop involving Cdc25p activation and Wee1p inactivation at the exit from mitosis. This disruption is temporally regulated to occur only after Cdk1p activity wanes, involving a mechanism of direct inhibition of Clp1p phosphatase activity through Cdk1p dependent phosphorylation during early mitosis. Clp1p also participates in an auto-amplification loop during mitotic exit as it auto-catalytically reverses the inhibitory phosphorylation events to increase its activity, and prevents further inhibition of its activity by attenuating Cdk1p activity. Together, these findings point to a simple regulatory circuit that couples Cdk1p activation with its inactivation mediated through regulation of Clp1p phosphatase activity.
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