ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1.
4E-BP1 plays a major role in translation by inhibiting cap-dependent translation initiation. Several reports have investigated the regulation of 4E-BP1 phosphorylation, which varies along with cell differentiation and upon various stimulations, but very little is known about the regulation of its expression. In a first part, we show that the expression of 4E-BP1 protein and transcript decreases in hematopoietic cell lines cultivated in the presence of phorbol 12-myristate 13-acetate (PMA). This decrease depends on the activation of the ERK/mitogen-activated protein kinases. 4E-BP1 expression also decreases when the p38/mitogen-activated protein kinase pathway is activated by granulocyte/macrophage colony-stimulating factor but to a lesser extent than with PMA. In a second part, we examine how 4e-bp1 promoter activity is regulated. PMA and granulocyte/macrophage colony-stimulating factor induce Egr-1 expression through ERK and p38 activation, respectively. Using a dominant negative mutant of Egr, ZnEgr, we show that this transcription factor is responsible for the inhibition of 4e-bp1 promoter activity. In a third part we show that histidine decarboxylase, whose activity and expression are inversely correlated with 4E-BP1 expression, is a potential target for the translational machinery. These data (i) are the first evidence of a new role of ERK and p38 on the translational machinery and (ii) demonstrate that 4E-BP1 is a new target for Egr-1.
Rolli-Derkinderen
Malvyne
M
CNRS FRE 2444, Université René Descartes Paris V, Hôpital Necker, Institut Federatif de Recherche Necker Enfants Malades, 75015 Paris, France.
Machavoine
François
F
Baraban
Jay M
JM
Grolleau
Annabelle
A
Beretta
Laura
L
Dy
Michel
M
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007038:Hypotonic Solutions; D017874:Immediate-Early Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D048670:MAP Kinase Kinase 4; D048290:Mitogen-Activated Protein Kinase 11; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000235:genetics*; D020218:Response Elements; D020123:Sirolimus / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002867:Chromones; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; C087000:EIF4EBP1 protein, human; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D007038:Hypotonic Solutions; D017874:Immediate-Early Proteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D010768:Phosphoserine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D006632:Histamine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D048031:JNK Mitogen-Activated Protein Kinases; D048290:Mitogen-Activated Protein Kinase 11; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D006640:Histidine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus