Proto oncogene/eukaryotic translation initiation factor (eIF) 4E attenuates mevalonate-mediated regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase synthesis.
The rate-limiting enzyme for mevalonate synthesis in mammalian cells is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Products of mevalonate synthesis are required for cell cycle progression as well as cell growth and survival. In tumor cells, HMG-CoA reductase is generally elevated because of attenuated sterol-mediated regulation of transcription. However, tumor cell HMG-CoA reductase remains sensitive to post-transcriptional regulation by mevalonate-derived isoprenoid intermediates of cholesterol synthesis. Isoprenoids suppress HMG-CoA reductase synthesis through a mechanism that reduces initiation of translation on HMG-CoA reductase mRNA. Because HMG-CoA reductase mRNA transcripts have 5'-untranslated regions (UTR) that are GC rich and contain stable secondary structure, we tested the hypothesis that overexpression of eIF4E would attenuate isoprenoid-mediated regulation of HMG-CoA reductase. eIF4E is elevated in many tumor cells and behaves as a proto-oncogene by aberrantly translating mRNAs whose translation is normally suppressed by 5-UTRs that are GC rich. A CHO cell line expressing high levels of eIF4E (rb4E) was developed by infecting cells with retroviruses containing a full-length mouse cDNA for eIF4E. Levels of reductase synthesis were elevated fivefold in rb4E cells compared to noninfected CHO cells; HMG-CoA reductase mRNA levels were not increased in rb4E cells compared to normal CHO cells. Total cellular protein synthesis was only increased by approximately 15% in rb4E cells compared to CHO cells. The mTOR inhibitor rapamycin lowered HMG-CoA reductase synthesis by 50 and 60% in rb4E and CHO cells, respectively; no equivalent effect was observed for HMG-CoA reductase mRNA levels with rapamycin treatment. These results indicate that HMG-CoA reductase mRNA is in a class of mRNAs with highly structured 5'-UTRs whose m(7)GpppX cap-dependent translation is closely linked to the rapamycin-sensitive mitogen activated pathway for protein synthesis.
Buechler
Robbie D
RD
Department of Neurology, Duke University Medical Center, Erwin Road, Durham, North Carolina, USA.
Peffley
Dennis M
DM
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000235:genetics*; D008798:Mevalonic Acid / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid