Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro.

Correll, Carl C.; Edwards, Peter A.

doi:10.1016/s0021-9258(17)42396-9

Cited by 71 publications

(16 citation statements)

References 40 publications

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“…Previous studies have demonstrated that nonsterol products of mevalonate metabolism are important posttranscriptional regulators of HMGR activity, functioning both as translational repressors and as stimulators of protein degradation (3,(11)(12)(13)(14)(15)(16)(17)(18). The majority of these studies have concluded that farnesol, derived from FPP hydrolysis, or metabolites of farnesol are likely NSRR candidates (10,11,19,21,22).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of these studies have concluded that farnesol, derived from FPP hydrolysis, or metabolites of farnesol are likely NSRR candidates (10,11,19,21,22). However, several studies have questioned the importance of farnesol in HMGR regulation or have implicated the stable SQS reaction intermediate, PSQPP, or its metabolites as the true NSRR (18,20,23).…”

Section: Discussionmentioning

confidence: 99%

“…Much evidence in the literature supports the role of farnesol or farnesol metabolites as putative NSRRs. First, accelerated HMGR degradation can be induced in permeabilized CHO (20,22) and met-18b-2 (18,19) cells by administration of mevalonate (18,20), FPP (19,20) or farnesol (19,22), but not by a nonhydrolyzable FPP analog (20,22), suggesting that FPP action is due to its hydrolysis to farnesol. Second, FPP-mediated HMGR degradation can be prevented by FPPase inhibition (19,22), and this inhibition can be overcome by addition of farnesol (22), further suggesting a requirement for FPP hydrolysis for activity.…”

Section: Discussionmentioning

confidence: 99%

“…Both sterol and nonsterol products of mevalonate metabolism are required for full suppression of HMGR expression (3,15,16). For example, sterols are thought to mediate HMGR transcriptional repression (9); nonsterol meva-lonate metabolites are thought to mediate HMGR translational repression (13,15); and both sterols and nonsterol mevalonate metabolites are thought to synergystically enhance HMGR degradation (15,16,18).…”

mentioning

confidence: 99%

“…For example, previous reports have demonstrated that these NSRRs are derived from farnesyl pyrophosphate (FPP) but are not FPP itself. These reports have also indicated that these NSRRs are neither dolichol, ubiquinone, isopentenyl adenine, geranylgeranyl pyrophosphate (GGPP), nor post-squalene cholesterolgenic metabolites (3,11,12,(18)(19)(20)(21). More recent studies have implicated FPP hydrolysis products (e.g., farnesol, farnesyl phosphate, farnesoic acids; 11,19,21,22), the squalene synthetase (SQS) reaction products presqualene pyrophosphate (PSQPP) and squalene (18,20,23), and their respective metabolites, as putative NSRRs, although the existence of specific prenylated proteins that function as mediators of these effects has not been ruled out (2,24).…”

mentioning

confidence: 99%

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HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonate-derived nonsterol regulator production in cultured IM-9 cells

Lindsey

1999

Journal of Lipid Research

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The activity of HMG-CoA reductase (HMGR) is tightly regulated, in part through post-transcriptional mechanisms that are mediated by nonsterol products of mevalonate metabolism. Previous reports have suggested that these mediators are derived from farnesyl pyrophosphate (FPP). Recent studies have implicated FPP hydrolysis products (e.g., farnesol), the squalene synthetase (SQS) reaction products presqualene pyrophosphate (PSQPP) and squalene, or their metabolites. To distinguish among these possible mediators, we evaluated the ability of HMGR and SQS inhibitors to induce compensatory increases in HMGR activity in cultured IM-9 cells. Mevinolin (HMGR inhibitor) produced predicted increases in HMGR activity that were related to the degree of cholesterolgenesis inhibition (e.g., 4-fold, 9-fold, and 17-fold increases relative to 50%, 76%, and 90% inhibition, respectively). By contrast, a variety of structurally distinct reversible, competitive, first half-reaction SQS inhibitors all reduced cholesterolgenesis by up to 90% with no appreciable increases in HMGR activity. These observations strongly suggest that nonsterol-mediated posttranscriptional mechanisms regulating HMGR activity remain intact after SQS first half-reaction inhibition, indicating that nonsterol regulator production is independent of SQS action and ruling out PSQPP, squalene and their metabolites as possible mediators. Unexpectedly, the SQS mechanism-based irreversible inactivator, zaragozic acid A (ZGA) exhibited the greatest degree of HMGR modulation, producing 5-fold, 11-fold, and 40-fold increases in HMGR activity at concentrations that produced 25%, 50%, and 75% cholesterolgenesis inhibition, respectively. The markedly greater magnitude of HMGR stimulation by ZGA versus mevinolin at similar levels of cholesterolgenesis inhibition suggests that ZGA may directly interfere with the production or action of the nonsterol regulator. -Petras, S. F., S. Lindsey, and H. J. Harwood, Jr. HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonatederived nonsterol regulator production in cultured IM-9 cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonate-derived nonsterol regulator production in cultured IM-9 cells

Lindsey

1999

Journal of Lipid Research

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In vivo iodination of a misfolded proinsulin reveals co-localized signals for Bip binding and for degradation in the ER.

et al. 1995

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The signal for degradation of proteins in the endoplasmic reticulum (ER) is thought to be the exposure of internal domains which are buried when the protein has adopted its correct conformation and which are also exposed in assembly intermediates. This raises the question of why the intermediates are not degraded. We developed a system based on the peroxidase‐catalyzed iodination of tyrosine residues which continuously monitors the exposure of internal domains of proinsulin. In CHO cells this system discriminated between assembly intermediates of wild type (wt) proinsulin and misfolded proinsulin, as shown by the exclusive iodination of a misfolded mutant which was finally degraded in the ER. Iodination in vitro showed that the assembly intermediates of wt proinsulin also exposed internal domains. This iodination was inhibited by the addition of the molecular chaperone Bip which was co‐immunoprecipitated with proinsulin in CHO cells. The results obtained with the mutant proinsulin support the assumption that exposed internal domains represent the signal for degradation in the ER. Observations of wt proinsulin show that Bip masks internal domains of normal assembly intermediates during the entire assembly process, thereby suppressing their degradation. We propose that internal domains contain co‐localized signals for Bip binding and for degradation.

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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

Buechler

Peffley

2004

Molecular Carcinogenesis

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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.

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Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro.

Cited by 71 publications

References 40 publications

HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonate-derived nonsterol regulator production in cultured IM-9 cells

HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonate-derived nonsterol regulator production in cultured IM-9 cells

In vivo iodination of a misfolded proinsulin reveals co-localized signals for Bip binding and for degradation in the ER.

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

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