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XB-ART-43804
Mol Biol Cell. April 15, 2011; 22 (8): 1191-206.

Mitotic progression becomes irreversible in prometaphase and collapses when Wee1 and Cdc25 are inhibited.

Potapova TA , Sivakumar S , Flynn JN , Li R , Gorbsky GJ .


Abstract
Mitosis requires precise coordination of multiple global reorganizations of the nucleus and cytoplasm. Cyclin-dependent kinase 1 (Cdk1) is the primary upstream kinase that directs mitotic progression by phosphorylation of a large number of substrate proteins. Cdk1 activation reaches the peak level due to positive feedback mechanisms. By inhibiting Cdk chemically, we showed that, in prometaphase, when Cdk1 substrates approach the peak of their phosphorylation, cells become capable of proper M-to-G1 transition. We interfered with the molecular components of the Cdk1-activating feedback system through use of chemical inhibitors of Wee1 and Myt1 kinases and Cdc25 phosphatases. Inhibition of Wee1 and Myt1 at the end of the S phase led to rapid Cdk1 activation and morphologically normal mitotic entry, even in the absence of G2. Dampening Cdc25 phosphatases simultaneously with Wee1 and Myt1 inhibition prevented Cdk1/cyclin B kinase activation and full substrate phosphorylation and induced a mitotic "collapse," a terminal state characterized by the dephosphorylation of mitotic substrates without cyclin B proteolysis. This was blocked by the PP1/PP2A phosphatase inhibitor, okadaic acid. These findings suggest that the positive feedback in Cdk activation serves to overcome the activity of Cdk-opposing phosphatases and thus sustains forward progression in mitosis.

PubMed ID: 21325631
PMC ID: PMC3078080
Article link: Mol Biol Cell.
Grant support: 2R01GM050412 NIGMS NIH HHS , R01 GM050412-17 NIGMS NIH HHS , R01 GM050412-18 NIGMS NIH HHS , R01 GM050412 NIGMS NIH HHS

Genes referenced: ccnb1 ccnb1.2 cdc20 cdc25c cdc27 cdh1 cdk1 eif3a hist2h2be lmnb1 mastl myt1 npy4r ppp2r4 psmd6 rasgrf1 tuba4b wee1

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