4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation.

Abstract : Assembly of the multi-subunit eukaryotic translation initiation factor-4F (eIF4F) is critical for protein synthesis and cell growth and proliferation. eIF4F formation is regulated by the translation-inhibitory protein 4E-BP1. While proliferation factors and intracellular pathways that impinge upon 4E-BP1 phosphorylation have been extensively studied, how they control 4E-BP1 expression remains unknown. Here, we show that Smad4, a transcription factor normally required for TGFbeta-mediated inhibition of normal cell proliferation, enhances 4E-BP1 gene-promoter activity through binding to a conserved element. 4E-BP1 expression is specifically modulated by treatment with TGFbeta and by manipulations of the natural Smad4 regulators (co-Smads) in cells isolated from Smad4(+/+) human tumours, whereas no response is observed in cells isolated from Smad4(-/-) human tumours or in cells where Smad4 has been knocked down by specific siRNAs. In addition, cells where 4E-BP1 has been knocked down (inducible shRNAs in human pancreatic cancer cells or siRNAs in non-malignant human keratinocytes) or has been knocked out (mouse embryonic fibroblasts isolated from 4E-BP1(-/-) mice) proliferate faster and are resistant to the antiproliferative effect of TGFbeta. Thus, 4E-BP1 gene appears critical for TGFbeta/Smad4-mediated inhibition of cell proliferation.
Type de document :
Article dans une revue
EMBO Journal, EMBO Press, 2009, 28 (22), pp.3514-22. 〈10.1038/emboj.2009.291〉
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Soumis le : vendredi 16 avril 2010 - 16:52:37
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Rania Azar, Amandine Alard, Christiane Susini, Corinne Bousquet, Stéphane Pyronnet. 4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation.. EMBO Journal, EMBO Press, 2009, 28 (22), pp.3514-22. 〈10.1038/emboj.2009.291〉. 〈inserm-00473918〉



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