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Proto oncogene/eukaryotic translation initiation factor (eIF) 4E attenuates mevalonate‐mediated regulation of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase synthesis
Author(s) -
Buechler Robbie D.,
Peffley Dennis M.
Publication year - 2004
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20039
Subject(s) - reductase , biology , hmg coa reductase , mevalonate pathway , eif4e , hydroxymethylglutaryl coa reductase , coenzyme a , 7 dehydrocholesterol reductase , protein biosynthesis , mevalonic acid , messenger rna , biochemistry , microbiology and biotechnology , translation (biology) , enzyme , gene
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. © 2004 Wiley‐Liss, Inc.