Gastrin induces phosphorylation of eIF4E binding protein 1 and translation initiation of ornithine decarboxylase mRNA.
Gastrin via its G-protein coupled specific receptor induces transcription of c-fos and c-jun genes through a ras-MAPK pathway. Ornithine Decarboxylase (ODC), a growth regulated proto-oncogene, was chosen to investigate gastrin effects on translation initiation of mRNAs exhibiting a 5'UnTranslated Region (5'UTR) responsible for translation repression in quiescent cells. In AR4-2J tumoral cells, we first demonstrated that gastrin increases ODC mRNA translation. Transient transfections with various CAT chimeric constructs suggested a direct involvement of the 5'UTR in this observation. Translation of this group of mRNAs is enhanced by the availability of the cap-binding protein (eIF4E) that is increased after phosphorylation of its specific binding protein eIF4E-BP1. We found that AR4-2J cells over-expressed eIF4E protein which was not modulated by gastrin treatment. Rapamycin which inhibits 4E-BP1 phosphorylation, completely prevents gastrin-mediated increase of ODC translation indicating that 4E-BP1 could be involved in regulating ODC translation. Implication of 4E-BP1 in mediating gastrin effects is corroborated by the capacity of the ligand to affect 4E-BP1 phosphorylation. These results indicate that gastrin enhances ornithine decarboxylase mRNA translation through a rapamycin sensitive pathway and provide the first evidence in the control of 4E-BP1 phosphorylation after occupancy of a G protein-coupled receptor.
Pyronnet
S
S
INSERM U151, Institut Louis Bugnard, IFR 31, CHU Rangueil, Toulouse, France.
Gingras
A C
AC
Bouisson
M
M
Kowalski-Chauvel
A
A
Seva
C
C
Vaysse
N
N
Sonenberg
N
N
Pradayrol
L
L
D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins; D004790:Enzyme Induction / Q000187:drug effects; D005755:Gastrins / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics*; D065108:Ornithine Decarboxylase Inhibitors; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D010750:Phosphoproteins / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D012097:Repressor Proteins / Q000494:pharmacology; D020123:Sirolimus; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D005755:Gastrins; D047908:Intracellular Signaling Peptides and Proteins; D065108:Ornithine Decarboxylase Inhibitors; D010750:Phosphoproteins; D011090:Polyenes; D012333:RNA, Messenger; D012097:Repressor Proteins; D009955:Ornithine Decarboxylase; D020123:Sirolimus