Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1.
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.
Azar
R
R
Département Cancer, INSERM U858, Institut de Médecine Moléculaire de Rangueil, BP 84225, 31432, Toulouse Cedex 4, France.
Najib
S
S
Lahlou
H
H
Susini
C
C
Pyronnet
S
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002460:Cell Line; D004789:Enzyme Activation; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D009955:Ornithine Decarboxylase; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D012097:Repressor Proteins; C087000:EIF4EBP1 protein, human