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Translation Initiation Factor 4E Inhibits Differentiation of Erythroid Progenitors

Montserrat Blázquez-Domingo ,^, Godfrey Grech, and Marieke von Lindern^*

Department of Hematology, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands

Received 1 February 2005/ Returned for modification 21 March 2005/ Accepted 10 July 2005

Stem cell factor (SCF) delays differentiation and enhances the expansion of erythroid progenitors. Previously, we performed expression-profiling experiments to link signaling pathways to target genes using polysome-bound mRNA. SCF-induced phosphoinositide-3-kinase (PI3K) appeared to control polysome recruitment of specific mRNAs associated with neoplastic transformation. To evaluate the role of mRNA translation in the regulation of expansion versus differentiation of erythroid progenitors, we examined the function of the eukaryote initiation factor 4E (eIF4E) in these cells. SCF induced a rapid and complete phosphorylation of eIF4E-binding protein (4E-BP). Overexpression of eIF4E did not induce factor-independent growth but specifically impaired differentiation into mature erythrocytes. Overexpression of eIF4E rendered polysome recruitment of mRNAs with structured 5' untranslated regions largely independent of growth factor and resistant to the PI3K inhibitor LY294002. In addition, overexpression of eIF4E rendered progenitors insensitive to the differentiation-inducing effect of LY294002, indicating that control of mRNA translation is a major pathway downstream of PI3K in the regulation of progenitor expansion.

These authors contributed equally to this work.

Present address: Federation of European Microbiology Societies, 2628 CL Delft, The Netherlands.

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