Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1. - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Cellular and Molecular Life Sciences Year : 2008

Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1.

Abstract

The suppressor of translation initiation 4E-BP1 functions as a key regulator in cellular growth, differentiation, apoptosis and survival. While the control of 4E-BP1 activity via phosphorylation has been widely studied, the molecular mechanisms and the signaling pathways that govern 4E-BP1 gene expression are largely unknown. Here we show that inactivation of phosphatidylinositol 3-kinase (PI3K) consequent to stable expression of the antiproliferative somatostatin receptor 2 (sst2) in pancreatic cancer cells leads to transcriptional accumulation of the hypophosphorylated forms of 4E-BP1 protein. In cancer cells, while 4E-BP1 gene promoter is maintained repressed in a PI3K-dependent mechanism, sst2-dependent inactivation of the PI3K/Akt pathway releases 4E-BP1 gene transcription. Furthermore, the use of a pharmacological inhibitor and dominant-negative or -positive mutants of PI3K all affect 4E-BP1 protein expression and promoter activity in different cell lines. These data show that, in addition to inactivation of 4E-BP1 via hyperphosphorylation, signaling through the PI3K pathway silences 4E-BP1 gene transcription.

Dates and versions

inserm-00420103 , version 1 (28-09-2009)

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Cite

R. Azar, Souad Najib, H. Lahlou, Christiane Susini, Stéphane Pyronnet. Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1.. Cellular and Molecular Life Sciences, 2008, 65 (19), pp.3110-7. ⟨10.1007/s00018-008-8418-2⟩. ⟨inserm-00420103⟩
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