Journal
JOURNAL OF CELL BIOLOGY
Volume 178, Issue 3, Pages 371-385Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200703202
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Funding
- NCI NIH HHS [T32 CA009151, R56 CA078343, R01 CA078343, CA09151, CA78343] Funding Source: Medline
- NIGMS NIH HHS [R01 GM054811, GM60439, R01 GM060439, GM54811] Funding Source: Medline
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Overexpression of cyclin E, an activator of cyclindependent 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 (APC(Cdh1)) activity that persists as cells progress up to and through the early stages of mitosis, resulting in the abnormal accumulation of ApC(Cdh1) 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.
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