HER2 signaling enhances 5'UTR-mediated translation of c-Myc mRNA.
The increased levels of c-Myc protein observed previously in an ovarian carcinoma cell line stably transfected to express HER2 has suggested a role for the HER2 pathway in c-Myc expression. Analysis of HER2-transfected cells stimulated with heregulin beta1 (HRG) revealed increased c-Myc protein levels but not a corresponding increase in c-Myc mRNA expression or any change in c-Myc protein half-life. Transfection of HER2-overexpressing cells with a construct containing the 5' untranslated region (5'UTR) of c-Myc mRNA originated from the P2 promoter and placed upstream of the Renilla luciferase gene, enhanced reporter expression upon stimulation with HRG. The HRG-mediated increase in reporter activity correlated with the HRG-mediated induction observed for c-Myc protein, identifying the P2-derived leader (P2L) of c-Myc mRNA as the cis-element involved in c-Myc translational induction. Both the increase in c-Myc protein levels and P2L-enhanced translational activity were inhibited by the PI3K inhibitor wortmannin. Together, these results demonstrate that HRG stimulation of HER2 overexpressing cells leads to enhanced c-Myc protein synthesis through activation of the PI3K/Akt/mTOR pathway and that the P2L of c-Myc mRNA is the element responsible for induction of c-Myc translation.
Galmozzi
Enrico
E
Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
Casalini
Patrizia
P
Iorio
Marilena Valeria
MV
Casati
Barbara
B
Olgiati
Clelia
C
Ménard
Sylvie
S
D020121:5' Untranslated Regions / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002999:Clone Cells; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D018734:Genes, erbB-2; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin
D020121:5' Untranslated Regions; D000730:Androstadienes; D003513:Cycloheximide; D003609:Dactinomycin; D004791:Enzyme Inhibitors; D008156:Luciferases; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C087230:heregulin beta1; C546842:MTOR protein, human; C494918:AKT1 protein, human