Proto oncogene/eukaryotic translation initiation factor (eIF) 4E attenuates mevalonate-mediated regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase synthesis

Molecular Carcinogenesis
Robbie D Buechler, Dennis M Peffley

Abstract

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. Le...Continue Reading

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Citations

Aug 30, 2008·Archivum Immunologiae Et Therapiae Experimentalis·Clovis Orlando da FonsecaThereza Quirico-Santos
Mar 30, 2012·Expert Reviews in Molecular Medicine·Tabetha Sundin, Patricia Hentosh
Jan 4, 2013·Molecular and Cellular Biochemistry·Tabetha SundinPatricia Hentosh

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