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Deregulated cyclin E induces chromosome instability

Nature volume 401, pages 297–300 (1999)Cite this article

Abstract

Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (Cdk2), is an important regulator of entry into S phase in the mammalian cell cycle. In normal dividing cells, cyclin E accumulates at the G1/S-phase boundary and is degraded as cells progress through S phase1,2. However, in many human tumours cyclin E is overexpressed3 and the levels of protein and kinase activity are often deregulated relative to the cell cycle4,5,6,7. It is not understood how alterations in expression of cyclin E contribute to tumorigenesis. Here we show that constitutive cyclin-E overexpression in both immortalized rat embryo fibroblasts and human breast epithelial cells results in chromosome instability (CIN). In contrast, analogous expression of cyclin D1 or A does not increase the frequency of CIN. Cyclin-E-expressing cells that exhibit CIN have normal centrosome numbers. However, constitutive overexpression of cyclin E impairs S-phase progression, indicating that aberrant regulation of this process may be responsible for the CIN observed. These results indicate that downregulation of cyclin-E/Cdk2 kinase activity following the G1/S-phase transition may be necessary for the maintenance of karyotypic stability.

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Figure 1: Chromosomal distributions of REFs capable of the conditional deregulated overexpression of various human cyclins.
Figure 2: More detailed karyotypic analysis of cyclin-E-expressing cells.
Figure 3: Cyclin E(T380A) induced CIN in human breast epithelial cells.

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Acknowledgements

We thank T. Tisty for the rat cDNA probes, G. Wahl for help with gene-amplification assays and M. Smeets for assistance with cell-cycle experiments. Recombinant adenoviruses were provided by J. Cogswell and S. Neill (Glaxo Wellcome). This work was supported by a grant from the NCI. C.H.S. is supported by a special fellowship from the LSA.

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  1. Department of Molecular Biology, MB-7, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, 92037, California, USA

    Charles H. Spruck, Kwang-Ai Won & Steven I. Reed

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  1. Charles H. Spruck
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Correspondence to Steven I. Reed.

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Spruck, C., Won, KA. & Reed, S. Deregulated cyclin E induces chromosome instability. Nature 401, 297–300 (1999). https://doi.org/10.1038/45836

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