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Published online July 30, 2007
doi:10.1083/jcb.200703202
The Journal of Cell Biology, Vol. 178, No. 3, 371-385
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Keck et al.
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Article

 Cyclin E overexpression impairs progression through mitosis by inhibiting APCCdh1

Jamie M. Keck1, Matthew K. Summers2, Donato Tedesco1, Susanna Ekholm-Reed1, Li-Chiou Chuang1, Peter K. Jackson2, and Steven I. Reed1

1 Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305

Correspondence to Steven I. Reed: sreed{at}scripps.edu

Overexpression of cyclin E, an activator of cyclin-dependent kinase 2, has been linked to human cancer. In cell culture models, the forced expression of cyclin E leads to aneuploidy and polyploidy, which is consistent with a direct role of cyclin E overexpression in tumorigenesis. In this study, we show that the overexpression of cyclin E has a direct effect on progression through the latter stages of mitotic prometaphase before the complete alignment of chromosomes at the metaphase plate. In some cases, such cells fail to divide chromosomes, resulting in polyploidy. In others, cells proceed to anaphase without the complete alignment of chromosomes. These phenotypes can be explained by an ability of overexpressed cyclin E to inhibit residual anaphase-promoting complex (APCCdh1) activity that persists as cells progress up to and through the early stages of mitosis, resulting in the abnormal accumulation of APCCdh1 substrates as cells enter mitosis. We further show that the accumulation of securin and cyclin B1 can account for the cyclin E–mediated mitotic phenotype.

M.K. Summers' and P.K. Jackson's present address is Genentech, Inc., South San Francisco, CA 94080.

D. Tedesco's present address is Berlex, Inc., Richmond, CA 94806.

Abbreviations used in this paper: APC, anaphase-promoting complex; Cdk, cyclin-dependent kinase; EV, empty vector; IME, immortalized mammary epithelial; WT, wild type.


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