Spatial Positive Feedback at the Onset of Mitosis

• Published in: Cell Vol. 149; no. 7; pp. 1500 - 1513
• Main Authors: Santos, Silvia D.M., Wollman, Roy, Meyer, Tobias, Ferrell, James E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22-06-2012
• Subjects: Active Transport, Cell Nucleus - drug effects; CDC2 Protein Kinase - metabolism; Cell Nucleus - metabolism; Cyclin B1 - analysis; Cyclin B1 - metabolism; cyclins; cytoplasm; Feedback; HeLa Cells; Humans; interphase; microscopy; Mitosis; Models, Statistical; Phosphorylation; Sirolimus - analogs & derivatives
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.05.028

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.
[Display omitted]
► The onset of mitosis relies on spatial positive feedback ► Cyclin B1 phosphorylation and nuclear translocation reinforce each other ► Cyclin B1 phosphorylation allows it to bind to chromatin ► Spatial feedback ensures that mitotic entry is decisive and irreversible
The translocation of Cdk-cyclin B1 from the cytoplasm to the nucleus is part of the trigger that initiates mitosis. A positive feedback loop, in which nuclear translocation and phosphorylation of cyclin B1 reinforce each other, ensures that mitosis entry is robust and irreversible.