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Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism

Oncogene volume 24, pages 4851–4860 (2005)Cite this article

Abstract

Initial chemotherapeutic treatment triggers a stress-related response, which can lead to an increase in the expression of survival proteins. In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state. We found that PTX induced the hyperphosphorylation of 4E-BP1 in the breast cancer cell line, MDA MB 231, which reduced its association with eIF-4E, but did not alter the expression and phosphorylation of eIF-4E. The hyperphosphorylation of 4E-BP1 correlated with G2/M accumulation and with an increase in the phosphorylation of cdk1 substrates. Cotreatment with a histone deacetylase inhibitor (an indirect inhibitor of cdk activity), purvalanol A and roscovitine (direct cdk inhibitors), and the reduction of cyclin B expression using RNA interference decreased the hyperphosphorylation of 4E-BP1 in PTX treated cells. The hyperphosphorylation of 4E-BP1 by PTX increased the association of eIF-4E with eIF-4G, whereas cotreatment with purvalanol A inhibited the association of eIF-4E with eIF-4G in PTX treated cells. Taken together, our data suggest that PTX-increases the functional level of eIF-4E by promoting the hyperphosphorylation and release of 4E-BP1 through a cdk1-dependent mechanism.

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Acknowledgements

The National Institute of Health Grant CA77614 supported this study.

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  1. Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, 800 Rose Street, Lexington, 40536, KY, USA

    Victoria L Greenberg & Stephen G Zimmer

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Correspondence to Stephen G Zimmer.

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Greenberg, V., Zimmer, S. Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism. Oncogene 24, 4851–4860 (2005). https://doi.org/10.1038/sj.onc.1208624

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