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. 1994 Jun;5(6):655–665. doi: 10.1091/mbc.5.6.655

Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in Saccharomyces cerevisiae.

D Dimster-Denk 1, M K Thorsness 1, J Rine 1
PMCID: PMC301081  PMID: 7949422

Abstract

In eukaryotic cells all isoprenoids are synthesized from a common precursor, mevalonate. The formation of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) is catalyzed by HMG-CoA reductase and is the first committed step in isoprenoid biosynthesis. In mammalian cells, synthesis of HMG-CoA reductase is subject to feedback regulation at multiple molecular levels. We examined the state of feedback regulation of the synthesis of the HMG-CoA reductase isozyme encoded by the yeast gene HMG1 to examine the generality of this regulatory pattern. In yeast, synthesis of Hmg1p was subject to feedback regulation. This regulation of HMG-CoA reductase synthesis was independent of any change in the level of HMG1 mRNA. Furthermore, regulation of Hmg1p synthesis was keyed to the level of a nonsterol product of the mevalonate pathway. Manipulations of endogenous levels of several isoprenoid intermediates, either pharmacologically or genetically, suggested that mevalonate levels may control the synthesis of Hmg1p through effects on translation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alani E., Cao L., Kleckner N. A method for gene disruption that allows repeated use of URA3 selection in the construction of multiply disrupted yeast strains. Genetics. 1987 Aug;116(4):541–545. doi: 10.1534/genetics.112.541.test. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barnes G., Hansen W. J., Holcomb C. L., Rine J. Asparagine-linked glycosylation in Saccharomyces cerevisiae: genetic analysis of an early step. Mol Cell Biol. 1984 Nov;4(11):2381–2388. doi: 10.1128/mcb.4.11.2381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Basson M. E., Thorsness M., Rine J. Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5563–5567. doi: 10.1073/pnas.83.15.5563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bergstrom J. D., Kurtz M. M., Rew D. J., Amend A. M., Karkas J. D., Bostedor R. G., Bansal V. S., Dufresne C., VanMiddlesworth F. L., Hensens O. D. Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):80–84. doi: 10.1073/pnas.90.1.80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beyer P., Kreuz K., Kleinig H. Separation of mevalonate phosphates and isopentenyl pyrophosphate by thin-layer chromatography and of short-chain prenyl phosphates by ion-pair chromatography on a high-performance liquid chromatography column. Methods Enzymol. 1985;111:248–252. doi: 10.1016/s0076-6879(85)11012-8. [DOI] [PubMed] [Google Scholar]
  7. Boeke J. D., LaCroute F., Fink G. R. A positive selection for mutants lacking orotidine-5'-phosphate decarboxylase activity in yeast: 5-fluoro-orotic acid resistance. Mol Gen Genet. 1984;197(2):345–346. doi: 10.1007/BF00330984. [DOI] [PubMed] [Google Scholar]
  8. Brown M. S., Goldstein J. L. Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res. 1980 Jul;21(5):505–517. [PubMed] [Google Scholar]
  9. Burnette W. N. "Western blotting": electrophoretic transfer of proteins from sodium dodecyl sulfate--polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem. 1981 Apr;112(2):195–203. doi: 10.1016/0003-2697(81)90281-5. [DOI] [PubMed] [Google Scholar]
  10. Casey W. M., Keesler G. A., Parks L. W. Regulation of partitioned sterol biosynthesis in Saccharomyces cerevisiae. J Bacteriol. 1992 Nov;174(22):7283–7288. doi: 10.1128/jb.174.22.7283-7288.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cuthbert J. A., Lipsky P. E. Inhibition by 6-fluoromevalonate demonstrates that mevalonate or one of the mevalonate phosphates is necessary for lymphocyte proliferation. J Biol Chem. 1990 Oct 25;265(30):18568–18575. [PubMed] [Google Scholar]
  12. Cuthbert J. A., Lipsky P. E. Negative regulation of cell proliferation by mevalonate or one of the mevalonate phosphates. J Biol Chem. 1991 Sep 25;266(27):17966–17971. [PubMed] [Google Scholar]
  13. Gilman M. Z., Chamberlin M. J. Developmental and genetic regulation of Bacillus subtilis genes transcribed by sigma 28-RNA polymerase. Cell. 1983 Nov;35(1):285–293. doi: 10.1016/0092-8674(83)90231-3. [DOI] [PubMed] [Google Scholar]
  14. Goldstein J. L., Brown M. S. Regulation of the mevalonate pathway. Nature. 1990 Feb 1;343(6257):425–430. doi: 10.1038/343425a0. [DOI] [PubMed] [Google Scholar]
  15. Guarente L., Mason T. Heme regulates transcription of the CYC1 gene of S. cerevisiae via an upstream activation site. Cell. 1983 Apr;32(4):1279–1286. doi: 10.1016/0092-8674(83)90309-4. [DOI] [PubMed] [Google Scholar]
  16. Hagen D. C., Sprague G. F., Jr Induction of the yeast alpha-specific STE3 gene by the peptide pheromone a-factor. J Mol Biol. 1984 Oct 5;178(4):835–852. doi: 10.1016/0022-2836(84)90314-0. [DOI] [PubMed] [Google Scholar]
  17. Hampton R. Y., Rine J. Regulated degradation of HMG-CoA reductase, an integral membrane protein of the endoplasmic reticulum, in yeast. J Cell Biol. 1994 Apr;125(2):299–312. doi: 10.1083/jcb.125.2.299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ito H., Fukuda Y., Murata K., Kimura A. Transformation of intact yeast cells treated with alkali cations. J Bacteriol. 1983 Jan;153(1):163–168. doi: 10.1128/jb.153.1.163-168.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jones K. A., Yamamoto K. R., Tjian R. Two distinct transcription factors bind to the HSV thymidine kinase promoter in vitro. Cell. 1985 Sep;42(2):559–572. doi: 10.1016/0092-8674(85)90113-8. [DOI] [PubMed] [Google Scholar]
  20. Nakanishi M., Goldstein J. L., Brown M. S. Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme. J Biol Chem. 1988 Jun 25;263(18):8929–8937. [PubMed] [Google Scholar]
  21. Parks L. W., Bottema C. D., Rodriguez R. J., Lewis T. A. Yeast sterols: yeast mutants as tools for the study of sterol metabolism. Methods Enzymol. 1985;111:333–346. doi: 10.1016/s0076-6879(85)11020-7. [DOI] [PubMed] [Google Scholar]
  22. Peffley D., Sinensky M. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase synthesis by a non-sterol mevalonate-derived product in Mev-1 cells. Apparent translational control. J Biol Chem. 1985 Aug 25;260(18):9949–9952. [PubMed] [Google Scholar]
  23. Porter J. W. Mevalonate kinase. Methods Enzymol. 1985;110:71–78. doi: 10.1016/s0076-6879(85)10061-3. [DOI] [PubMed] [Google Scholar]
  24. Schafer W. R., Kim R., Sterne R., Thorner J., Kim S. H., Rine J. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science. 1989 Jul 28;245(4916):379–385. doi: 10.1126/science.2569235. [DOI] [PubMed] [Google Scholar]
  25. Schiestl R. H., Gietz R. D. High efficiency transformation of intact yeast cells using single stranded nucleic acids as a carrier. Curr Genet. 1989 Dec;16(5-6):339–346. doi: 10.1007/BF00340712. [DOI] [PubMed] [Google Scholar]
  26. Schroepfer G. J., Jr Sterol biosynthesis. Annu Rev Biochem. 1981;50:585–621. doi: 10.1146/annurev.bi.50.070181.003101. [DOI] [PubMed] [Google Scholar]
  27. Sengstag C., Stirling C., Schekman R., Rine J. Genetic and biochemical evaluation of eucaryotic membrane protein topology: multiple transmembrane domains of Saccharomyces cerevisiae 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mol Cell Biol. 1990 Feb;10(2):672–680. doi: 10.1128/mcb.10.2.672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Servouse M., Karst F. Regulation of early enzymes of ergosterol biosynthesis in Saccharomyces cerevisiae. Biochem J. 1986 Dec 1;240(2):541–547. doi: 10.1042/bj2400541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sikorski R. S., Hieter P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics. 1989 May;122(1):19–27. doi: 10.1093/genetics/122.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Siperstein M. D., Fagan V. M. Feedback control of mevalonate synthesis by dietary cholesterol. J Biol Chem. 1966 Feb 10;241(3):602–609. [PubMed] [Google Scholar]
  31. Thorsness M., Schafer W., D'Ari L., Rine J. Positive and negative transcriptional control by heme of genes encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase in Saccharomyces cerevisiae. Mol Cell Biol. 1989 Dec;9(12):5702–5712. doi: 10.1128/mcb.9.12.5702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tsay Y. H., Robinson G. W. Cloning and characterization of ERG8, an essential gene of Saccharomyces cerevisiae that encodes phosphomevalonate kinase. Mol Cell Biol. 1991 Feb;11(2):620–631. doi: 10.1128/mcb.11.2.620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Van Arsdell S. W., Stetler G. L., Thorner J. The yeast repeated element sigma contains a hormone-inducible promoter. Mol Cell Biol. 1987 Feb;7(2):749–759. doi: 10.1128/mcb.7.2.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wright R., Basson M., D'Ari L., Rine J. Increased amounts of HMG-CoA reductase induce "karmellae": a proliferation of stacked membrane pairs surrounding the yeast nucleus. J Cell Biol. 1988 Jul;107(1):101–114. doi: 10.1083/jcb.107.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]

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