Mevalonate regulates polysome distribution and blocks translation-dependent suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA: Relationship to translational control

Peffley, Dennis M.; Gayen, Apurba K.

doi:10.1007/bf02254770

Cited by 12 publications

(20 citation statements)

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“…The results show the three splice variants, CB, CB(Ϫ2), and CB(Ϫ2,3), to be similarly distributed in the sucrose gradient. Thus, 60 -75% of each message was present in fractions 5-12, which contain polysomes (32). Similar proportions of the abundant constitutive mRNA for glyceraldehyde-3-phosphate dehydrogenase were found in these same fractions.…”

Section: Transcripts Missing Exons 2 and 3 From A375 Human Melanoma Cmentioning

confidence: 69%

“…2 and under "Experimental Procedures." Fraction 5 corresponds to the position of the 80 S ribosome peak (32). Shown are the amounts RNA or PCR product recovered in the indicated fractions as a percent of the total.…”

Section: Table I Distribution Of Variant Cathepsin B Mrnas In Polysommentioning

confidence: 99%

“…Polysome Isolation-Polysomes were analyzed by a modification of earlier procedures (31,32). Exponentially growing A375M cells (five 175-cm 2 flasks, ϳ20 ϫ 10 6 cells/flask) were fed 10 -12 h before harvesting.…”

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In VivoExpression of an Alternatively Spliced Human Tumor Message That Encodes a Truncated Form of Cathepsin B

Mehtani¹,

Gong²,

Panella³

et al. 1998

Journal of Biological Chemistry

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Cathepsin B is a lysosomal cysteine protease whose increased expression is believed to be linked to the malignant progression of tumors. Alternative splicing and the use of alternative transcription initiation sites in humans produce cathepsin B mRNAs that differ in their 5-and 3-untranslated ends. Some human tumors also contain cathepsin B-related transcripts that lack exon 3 which encodes the N-terminal signal peptide and 34 of the 62-amino acid inhibitory propeptide. In this study we show that one such transcript, CB(؊2,3), which is missing exons 2 and 3, is likely to be a functional message in tumors. Thus, CB(؊2,3) was found to be otherwise complete, containing the remainder of the cathepsin B coding sequence and the part of the 3-untranslated region that is common to all previously characterized cathepsin B mRNAs in humans. Its in vitro translation product can be folded to produce enzymatic activity against the cathepsin B-specific substrate, N ␣ -benzyloxycarbonyl-L-Arg-L-Arg-4-methylcoumaryl-7-amide. Endogenous CB(؊2,3) from the metastatic human melanoma cell line, A375M, co-sediments with polysomes, indicating that it engages the eukaryotic translation machinery in these cells. Epitope-tagged forms of the truncated cathepsin B from CB(؊2,3) are produced in amounts comparable to the normal protein after transient transfection into COS cells. Immunofluorescence microscopy and subcellular fractionation show this novel tumor form of cathepsin B to be associated with nuclei and other membranous organelles, where it is likely to be bound to the cytoplasmic face of the membranes. This subcellular distribution was different from the lysosomal pattern shown by the epitope-tagged, full-length cathepsin B in COS cells. These results indicate that the message missing exons 2 and 3 is likely to be translated into a catalytically active enzyme, and that alternative splicing (exon skipping) could contribute to the aberrant intracellular trafficking of cathepsin B that is observed in some human cancers.Cathepsin B is a lysosomal cysteine protease whose expression and trafficking are frequently altered in transformed and malignant cells (1). Both its association with the plasma membrane and its secretion have been linked to the increased capacity of human and rodent tumors to invade and metastasize (2-5). The association of cathepsin B with cell fractions containing plasma membrane-derived vesicles and endosomes was found to increase after transfection of a human breast epithelial cell line with the c-Ha-ras oncogene (6). Cathepsin B has been detected in nuclei from human ectocervical tumors and in basal and columnar cells of the normal and hyperplastic prostate (7,8). In human lung tumor cell lines cathepsin B activity was also localized to the endoplasmic reticulum, nuclear membrane, and plasma membrane (9). Forms of cathepsin B greater in size and stability than the mature, lysosomal form have been observed in tumors from humans and animals or in media conditioned by them (10 -13). At present, many of these findings ...

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Section: Transcripts Missing Exons 2 and 3 From A375 Human Melanoma Cmentioning

confidence: 69%

Section: Table I Distribution Of Variant Cathepsin B Mrnas In Polysommentioning

confidence: 99%

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In VivoExpression of an Alternatively Spliced Human Tumor Message That Encodes a Truncated Form of Cathepsin B

Mehtani¹,

Gong²,

Panella³

et al. 1998

Journal of Biological Chemistry

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“…Subsequently, the uncoupling of HMG CoA reductase activity from sterol-mediated feedback regulation was shown to occur in diverse tumors as well as in embryonic and differentiating tissues and in carcinogen-treated and regenerating liver (107)(108)(109)(110)(111)(112)(113)(114)(115). George and Goldfarb (108) reported that the elevated sterol feedback-resistant HMG CoA reductase activity in tumors retains sensitivity to feedback regulation by mevalonate; as delineated above, farnesol appears to be the mevalonate-derived nonsterol feedback mediator of both the translation of HMG CoA reductase mRNA (59,101) and HMG CoA reductase degradation (81,82). A second study detailing the anomalies in tumor HMG CoA reductase activity is depicted in a report by Bennis et al (115).…”

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confidence: 99%

“…The discrepancy between large changes in enzyme activity and rates of synthesis, independent of a change in HMG CoA reductase mRNA level, points to a translational control mechanism, one that is mediated by a nonsterol mevalonate-derived product of the mevalonate pathway. We found that a mevalonate-derived nonsterol product distal to farnesyl diphosphate and proximal to lanosterol in the sterol pathway (59) suppresses HMG CoA reductase synthesis by reducing the efficiency of HMG CoA reductase mRNA translation (59,101). Candidate regulatory signal molecules include squalene, farnesyl pyrophosphate or a derivative (farnesol), or farnesyl-pyrophosphate-generated inorganic pyrophosphate (102).…”

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Isoprenoid‐Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

Elson

Peffley

Hentosh

et al. 1999

Proc Soc Exp Biol Med

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Pure and mixed isoprenoid end products of plant mevalonate metabolism trigger actions that suppress 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. These actions modulate HMG CoA reductase mRNA translation and the proteolytic degradation of HMG CoA reductase. Such post-transcriptional events, we propose, are activated directly by acyclic isoprenoids and indirectly by cyclic isoprenoids. Isoprenoids, acting secondarily to the dominant transcriptional effector of sterologenesis, modestly lower cholesterol levels, if and only if, sterologenesis is not repressed by a saturating imput of dietary cholesterol. An anomaly associated with tumor growth-a sterol feedback-resistant HMG CoA reductase activity-ensures a pool of sterologenic pathway intermediates. Such intermediates provide lipophilic anchors essential for membrane attachment and biological activity of growth hormone receptors, nuclear lamins A and B, and oncogenic ras. Tumor HMG CoA reductase retains high sensitivity to the isoprenoid-mediated secondary regulation. Repression of mevalonate synthesis by plant-derived isoprenoids reduces ras and lamin B processing, arrests cells in G1, and initiates cellular apoptosis. This unique tumor cell-specific sensitivity allows isoprenoids to be used for tumor therapy, an application emulating that of the statins, but one free of adverse effects. When evaluated at levels provided by a typical diet, isoprenoids individually have no impact on cholesterol synthesis and tumor growth. Nonetheless, isoprenoid-mediated activities are additive, and, sometimes synergistic. Therefore, the combined actions of the estimated 23,000 isoprenoid constituents of plant materials, acting in concert with other chemopreventive phytochemicals, may explain the lowered cancer risk associated with a diet rich in plant products. In contrast, that lowering of cancer risk does not correspond to supplemental intake of other dietary factors associated with fruits, vegetables, and cereal grains, namely fiber, beta-carotene, vitamin C, and vitamin E, and only weakly to supplemental folate.

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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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Mevalonate regulates polysome distribution and blocks translation-dependent suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA: Relationship to translational control

Cited by 12 publications

References 58 publications

In VivoExpression of an Alternatively Spliced Human Tumor Message That Encodes a Truncated Form of Cathepsin B

In VivoExpression of an Alternatively Spliced Human Tumor Message That Encodes a Truncated Form of Cathepsin B

Isoprenoid‐Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

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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