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Molecular and Cellular Biology, February 2001, p. 1384-1392, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1384-1392.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

E2F4 Is Exported from the Nucleus in a CRM1-Dependent Manner

Stefan Gaubatz,1 Jacqueline A. Lees,2 Geoffrey J. Lindeman,1,dagger and David M. Livingston1,*

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115,1 and Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 021392

Received 11 October 2000/Returned for modification 9 November 2000/Accepted 16 November 2000

E2F is a family of transcription factors required for normal cell cycle control and for cell cycle arrest in G1. E2F4 is the most abundant E2F protein in many cell types. In quiescent cells, it is localized to the nucleus, where it is bound to the retinoblastoma-related protein p130. During entry into the cell cycle, the protein disappears from the nucleus and appears in the cytoplasm. The mechanism by which this change occurs has, in the past, been unclear. We have found that E2F4 is actively exported from the nucleus and that leptomycin B, a specific inhibitor of nuclear export, inhibits this process. E2F4 export is mediated by two hydrophobic export sequences, mutations in either of which result in export failure. Individual export mutants of E2F4, but not a mutant with inactivation of both export signals, can be efficiently excluded from the nucleus by forced coexpression of the nuclear export receptor CRM1. Similarly, CRM1 overexpression can prevent cell cycle arrest induced by the cyclin kinase inhibitor p16INK4a, an E2F4-dependent process. Taken together, these data suggest that nuclear export contributes to the regulation of E2F4 function, including its ability to regulate exit from G1 in association with a suitable pocket protein.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3074. Fax: (617) 632-4381. E-mail: David_Livingston{at}dfci.harvard.edu.

dagger Present address: Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

Molecular and Cellular Biology, February 2001, p. 1384-1392, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1384-1392.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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