Internal ribosome entry segment-mediated initiation of c-Myc protein synthesis following genotoxic stress.
Initiation of translation of the proto-oncogene c-myc can occur by either the cap-dependent scanning mechanism or by internal ribosome entry. The latter mechanism requires a complex RNA structural element that is located in the 5' untranslated region of c-myc, termed an internal ribosome entry segment (IRES). Recent work has shown that IRESs are used to maintain protein expression under conditions when cap-dependent translation initiation is compromised; for example, during mitosis, apoptosis and under conditions of cell stress, such as hypoxia or heat shock. Induction of genotoxic stress also results in a large reduction in global protein synthesis rates and therefore we investigated whether the c-myc IRES was active following DNA damage. As expected, in cells treated with either ethylmethane sulphonate or mitomycin C there was a large reduction in protein synthesis, although this was brought about by two different mechanisms. However, in each case the c-myc IRES was active and c-Myc protein expression was maintained. Finally we showed that the proteins required for this process are downstream of the p38 mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated protein kinase (ERK)/MEK(MAPK/ERK kinase) signalling pathways, since pre-treatment of cells with inhibitors of these pathways before DNA damage is initiated inhibits both c-myc IRES activity and expression of c-Myc protein.
Subkhankulova
T
T
Department of Biochemistry, University of Leicester, University Road, Leicester LE1 7RH, UK.
Mitchell
S A
SA
Willis
A E
AE
D020121:5' Untranslated Regions / Q000235:genetics; D015152:Blotting, Northern; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D006367:HeLa Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016685:Mitomycin / Q000494:pharmacology; D010442:Peptide Chain Initiation, Translational / Q000235:genetics*; D010766:Phosphorylation; D011233:Precipitin Tests; D014176:Protein Biosynthesis / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C000715470:MAS1 protein, human; D011500:Protein Synthesis Inhibitors; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014157:Transcription Factors; D016685:Mitomycin; D005020:Ethyl Methanesulfonate; D008156:Luciferases; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus