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Vol. 9, Issue 11, 3019-3030, November 1998

Regulation of the Anaphase-promoting Complex/Cyclosome by bimA^APC3 and Proteolysis of NIMA

Xiang S. Ye,^* Russell R. Fincher, Alice Tang, Aysha H. Osmani, and Stephen A. Osmani

Henry Hood Research Program, Weis Center for Research, Pennsylvania State University College of Medicine, Danville, Pennsylvania 17822

Surprisingly, although highly temperature-sensitive, the bimA1^APC3 anaphase-promoting complex/cyclosome (APC/C) mutation does not cause arrest of mitotic exit. Instead, rapid inactivation of bimA1^APC3 is shown to promote repeating oscillations of chromosome condensation and decondensation, activation and inactivation of NIMA and p34^cdc2 kinases, and accumulation and degradation of NIMA, which all coordinately cycle multiple times without causing nuclear division. These bimA1^APC3-induced cell cycle oscillations require active NIMA, because a nimA5 + bimA1^APC3 double mutant arrests in a mitotic state with very high p34^cdc2 H1 kinase activity. NIMA protein instability during S phase and G2 was also found to be controlled by the APC/C. The bimA1^APC3 mutation therefore first inactivates the APC/C but then allows its activation in a cyclic manner; these cycles depend on NIMA. We hypothesize that bimA^APC3 could be part of a cell cycle clock mechanism that is reset after inactivation of bimA1^APC3. The bimA1^APC3 mutation may also make the APC/C resistant to activation by mitotic substrates of the APC/C, such as cyclin B, Polo, and NIMA, causing mitotic delay. Once these regulators accumulate, they activate the APC/C, and cells exit from mitosis, which then allows this cycle to repeat. The data indicate that bimA^APC3 regulates the APC/C in a NIMA-dependent manner.

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^*   Present address: Infectious Diseases Research, Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285.
   Present address: Johns Hopkins School of Medicine, Department of Molecular Biology and Genetics, Baltimore, MD 21205.
   Corresponding author.

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Molecular Biology of the Cell
Vol. 9, 3019-3030, November 1998
Copyright © 1998 by The American Society for Cell Biology

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