Cell Cycle 2006 Oct 01;519:2268-74.

Aurora-A kinase and inhibitor-2 regulate the cyclin threshold for mitotic entry in Xenopus early embryonic cell cycles.

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The abrupt activation of CDK1 during mitotic entry requires suppression of CDK activity until a threshold concentration of cyclin B is synthesized, triggering the activation of a large pool of CDK. The cellular mechanisms that define the concentration of cyclin B at which the threshold occurs are unknown. Here we demonstrate that this threshold is regulated by Aurora-A kinase and phosphatase Inhibitor-2. In Xenopus CSF extracts that actively translate cyclin B1, immunodepletion of either endogenous xInhibitor-2 or endogenous xAurora-A caused delayed mitotic entry and normal timing was restored by addition of the respective recombinant proteins. Aurora-A depleted extracts also could be rescued by the addition of full-length xInhibitor-2, but not an xInhibitor-2 truncated of its PP1 binding motif. This demonstrates that inhibition of PP1 was required to compensate for the absence of Aurora-A. To test the hypothesis that the delays in mitotic entry in CSF extracts were due to increases in cyclin B thresholds, we employed interphase extracts, which are driven into mitosis by the addition of recombinant cyclin B in a nonlinear (threshold) dose-response. Neutralization of endogenous xInhibitor-2 or xAurora with antibodies increased the cyclin B threshold concentration. Alternatively, the addition of exogenous Aurora-A or Inhibitor-2 lowered the concentration of cyclin B that triggered CDK activation. Because the cyclin B threshold could be raised or lowered by changing the amount of either Aurora-A or Inhibitor-2, the results demonstrate these regulatory proteins are involved in a signaling loop required to create the switching behavior characteristic of mitotic entry.

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Species referenced: Xenopus
Genes referenced: aurka ccnb1 ccnb1.2 cdk1 npy4r