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Molecular Biology, Pathobiology and Genetics |
Department of Biological Sciences, Stanford University, Stanford, California
Requests for reprints: Guowei Fang, Department of Biological Sciences, Stanford University, 337 Campus Drive, Stanford, CA 94305-5020. Phone: 650-725-2762; Fax: 650-724-9945; E-mail: gwfang{at}stanford.edu.
Aurora B kinase, a subunit of the chromosomal passenger protein complex, plays essential roles in spindle assembly, chromosome bi-orientation, and cytokinesis. The kinase activity of Aurora B, which peaks in mitosis, is tightly controlled in the cell cycle. Modulation of Aurora B protein levels could partly account for the regulation of its kinase activity in the cell cycle. However, little is known on the molecular mechanism of regulation of Aurora B levels. Here, we examined Aurora B protein levels and confirmed that they fluctuate during the cell cycle, peaking in mitosis and dropping drastically in G1. This profile for Aurora B in the cell cycle is reminiscent of those for substrates of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase essential for mitotic progression. Indeed, Aurora B is a substrate of APC/C both in vitro and in vivo. Aurora B is efficiently ubiquitinated in an in vitro reconstituted system by APC/C that had been activated by Cdh1. The recognition of Aurora B by APC/C-Cdh1 is specific as it requires the presence of a conserved D-box at the COOH terminus of Aurora B. Furthermore, endogenous Aurora B and Cdh1 form a complex exclusively in mitotic cells. Degradation of Aurora B at the end of mitosis requires Cdh1 in vivo as a reduction of the Cdh1 level by RNA interference stabilizes the Aurora B protein. We conclude that, as a key mitotic regulator, Aurora B is regulated both by its activation during early mitosis and by its destruction by APC/C-Cdh1 in late mitosis and in G1.
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