Spatial positive feedback at the onset of mitosis.
Mitosis is triggered by the activation of Cdk1-cyclin B1 and its translocation from the cytoplasm to the nucleus. Positive feedback loops regulate the activation of Cdk1-cyclin B1 and help make the process irreversible and all-or-none in character. Here we examine whether an analogous process, spatial positive feedback, regulates Cdk1-cyclin B1 redistribution. We used chemical biology approaches and live-cell microscopy to show that nuclear Cdk1-cyclin B1 promotes the translocation of Cdk1-cyclin B1 to the nucleus. Mechanistic studies suggest that cyclin B1 phosphorylation promotes nuclear translocation and, conversely, nuclear translocation promotes cyclin B1 phosphorylation, accounting for the feedback. Interfering with the abruptness of Cdk1-cyclin B1 translocation affects the timing and synchronicity of subsequent mitotic events, underscoring the functional importance of this feedback. We propose that spatial positive feedback ensures a rapid, complete, robust, and irreversible transition from interphase to mitosis and suggest that bistable spatiotemporal switches may be widespread in biological regulation.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA. sdsantos@stanford.edu
Silvia D M
SD
Santos
Roy
R
Wollman
Tobias
T
Meyer
James E
JE
Ferrell
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D056744:Cyclin B1 / Q000032:analysis / Q000378:metabolism*; D005246:Feedback; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D015233:Models, Statistical; D010766:Phosphorylation; D020123:Sirolimus / Q000031:analogs & derivatives
C534699:CCNB1 protein, human; D056744:Cyclin B1; D016203:CDC2 Protein Kinase; D020123:Sirolimus