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Molecular and Cellular Biology, September 1999, p. 6041-6047, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cell Cycle Progression and Proliferation Despite 4BP-1 Dephosphorylation

Steven O. Marx1 and Andrew R. Marks1,2,*

Molecular Cardiology Program, Divisions of Cardiology and Circulatory Physiology, Department of Medicine,1 and Department of Pharmacology,2 Columbia University College of Physicians and Surgeons, New York, New York 10032

Received 7 January 1999/Returned for modification 17 March 1999/Accepted 26 May 1999

Proliferation and cell cycle progression in response to growth factors require de novo protein synthesis. It has been proposed that binding of the eukaryotic translation initiation factor 4E (eIF-4E) to the inhibitory protein 4BP-1 blocks translation by preventing access of eIF-4G to the 5' cap of the mRNA. The signal for translation initiation is thought to involve phosphorylation of 4BP-1, which causes it to dissociate from eIF-4E and allows eIF-4G to localize to the 5' cap. It has been suggested that the ability of the macrolide antibiotic rapamycin to inhibit 4BP-1 phosphorylation is responsible for the potent antiproliferative property of this drug. We now show that rapamycin-resistant cells exhibited normal proliferation despite dephosphorylation of 4BP-1 that allows it to bind to eIF-4E. Moreover, despite rapamycin-induced dephosphorylation of 4BP-1, eIF-4E-eIF-4G complexes (eIF-4F) were still detected. In contrast, amino acid withdrawal, which caused a similar degree of 4BP-1 dephosphorylation, resulted in dissociation of the eIF-4E-eIF-4G complex. Thus, 4BP-1 dephosphorylation is not equivalent to eIF-4E inactivation and does not explain the antiproliferative property of rapamycin.

* Corresponding author. Mailing address: Molecular Cardiology Program, Box 65, Columbia University College of Physicians & Surgeons, Rm 9-401, 630 West 168th St., New York, NY 10032. Phone: (212) 305-0270. Fax: (212) 305-3690. E-mail: arm42{at}columbia.edu.

Molecular and Cellular Biology, September 1999, p. 6041-6047, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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