Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1.
Cell Mol Life Sci
; 65(19): 3110-7, 2008 Oct.
Article
de En
| MEDLINE
| ID: mdl-18810319
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Phosphoprotéines
/
Protéines de répression
/
Transcription génétique
/
Phosphatidylinositol 3-kinases
/
Extinction de l'expression des gènes
/
Protéines adaptatrices de la transduction du signal
Limites:
Animals
/
Humans
Langue:
En
Journal:
Cell Mol Life Sci
Sujet du journal:
BIOLOGIA MOLECULAR
Année:
2008
Type de document:
Article
Pays d'affiliation:
France