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A more recent version of this article appeared on December 1, 2002
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Submitted on February 26, 2002
Revised on July 31, 2002
Accepted on September 9, 2002
1 Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, EN6 3LD, UK; and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, NC 27710-3686 (present address: Ribotargets Ltd., Granta Park, Cambridge, CB1 6GB, England)
2 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, NC 27710-3686
3 Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, EN6 3LD, UK
* Corresponding author. E-mail address: tim.hunt{at}cancer.org.uk.
Cdk2/cyclin E is imported into nuclei assembled in Xenopus egg extracts by a pathway that requires importin-
?and -ß (J. D. Moore et al. (1999). J. Cell Biol. 144, 213-224). Here, we identify a basic nuclear localization sequence (NLS) in the N-terminus of Xenopus cyclin E. Mutation of the NLS eliminated nuclear accumulation of both cyclin E and of Cdk2 and such versions of cyclin E were unable to trigger DNA replication. Addition of a heterologous nuclear localization sequence from SV40 large T antigen restored both nuclear targeting of Cdk2/cyclin E and DNA replication. We present evidence indicating that Cdk2/cyclin E complexes must become highly concentrated within nuclei to support replication, and find that cyclin A can trigger replication at much lower intranuclear concentrations. We confirmed that depletion of endogenous cyclin E increases the concentration of cyclin B required to promote entry into mitosis (see T.M. Guadagno and J.W. Newport (1996) Cell. 84, 73-82). In contrast to its inability to promote DNA replication, cyclin E lacking its NLS was able to cooperate with cyclin B in promoting mitotic entry.
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