A little Cdc20 goes a long way

A little Cdc20 goes a long way C dc20 drives mitotic cells from metaphase into anaphase. Once metaphase chromosomes are aligned at the center of the mitotic spindle, Cdc20 activates the E3 ubiquitin ligase APC/C to trigger the degradation of cyclin B1 and securin, allowing sister chromatids to separate and move toward opposite poles (1). Cdc20 is so essential for mitotic progression that mouse embryos lacking the protein fail to pass the two-cell stage (2). " It's easy to assume that you'll be in big trouble if you don't have near-normal levels of important proteins like Cdc20, " says Jan van Deursen, from the Mayo Clinic in Rochester, Minne-sota. " But what happens if there's enough Cdc20 for cells to get through mitosis but not enough for them to do it perfectly? " To fi nd out, van Deursen and colleagues generated a series of mice expressing progressively lower amounts of Cdc20 (3). Malureanu et al. made animals expressing as little as 15–20% of normal Cdc20 levels. Yet the mice seemed completely healthy. " We were very surprised, and also disappointed, " admits van Deursen. A closer look at isolated cells, however, revealed that aneuploidy—the presence of abnormal chromosome numbers—was increased in Cdc20 hypomorphic mice. " We looked at dividing cells and saw misaligned chromosomes, refl ecting problems with kinetochore–microtubule attachments, " van Deursen explains. Cdc20 hasn't been implicated in linking chromosomes to the spindle before , though a small portion of the protein localizes to kinetochores in wild-type cells. This local-ization was reduced in Cdc20-depleted cells, suggesting that Cdc20 could have a direct role in capturing microtubules to accurately segregate sister chromatids. Alternatively, lower Cdc20 levels could indirectly affect chromosome alignment by reducing APC/C's ability to target cyclin B1 and other mitotic proteins for destruction, resulting in the misregulation of kinetochore–microtubule attachments. Indeed, rather than gradually declining during metaphase, cyclin B1 levels increased as Cdc20 hypomorphic cells went through mitosis. Malureanu et al. found that cyclin B1 mRNA was translated during metaphase. Anaphase onset was delayed in Cdc20 hypomorphic cells, but blocking cyclin B1's mitotic synthesis reduced the protein's level and restored the timing of the metaphase-to-anaphase transition. Cyclin B1 was also synthesized in wild-type mitotic cells, though this is usually masked by the pro-tein's turnover at the hands of Cdc20 and the APC/C. Why would metaphase cells simultaneously synthesize and degrade cyclin B1? Perhaps, says van Deursen, because …