• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. Nov 1991; 11(11): 5417–5425.
PMCID: PMC361678

Regulation of IMP dehydrogenase gene expression by its end products, guanine nucleotides.

Abstract

To study the regulation of IMP dehydrogenase (IMPDH), the rate-limiting enzyme of guanine nucleotide biosynthesis, we examined the effects of nucleosides, nucleotides, nucleotide analogs, or the IMPDH inhibitor mycophenolic acid (MPA) on the steady-state levels of IMPDH mRNA. The results indicated that IMPDH gene expression is regulated inversely by the intracellular level of guanine ribonucleotides. We have shown that treatment with guanosine increased the level of cellular guanine ribonucleotides and subsequently reduced IMPDH steady-state mRNA levels in a time- and dose-dependent manner. Conversely, MPA treatment diminished the level of guanine ribonucleotides and increased IMPDH mRNA levels. Both of these effects on the steady-state level of IMPDH mRNA could be negated by cotreatment with guanosine and MPA. The down regulation of IMPDH gene expression by guanosine or its up regulation by MPA was not due to major changes in transcriptional initiation and elongation or mRNA stability in the cytoplasm but rather was due to alterations in the levels of the IMPDH mRNA in the nucleus. These results suggest that IMPDH gene expression is regulated by a posttranscriptional, nuclear event in response to fluctuations in the intracellular level of guanine ribonucleotides.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Abrahamsen MS, Morris DR. Cell type-specific mechanisms of regulating expression of the ornithine decarboxylase gene after growth stimulation. Mol Cell Biol. 1990 Oct;10(10):5525–5528. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Bender TP, Thompson CB, Kuehl WM. Differential expression of c-myb mRNA in murine B lymphomas by a block to transcription elongation. Science. 1987 Sep 18;237(4821):1473–1476. [PubMed]
  • Bentley DL, Groudine M. A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells. Nature. 1986 Jun 12;321(6071):702–706. [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Celano P, Baylin SB, Casero RA., Jr Polyamines differentially modulate the transcription of growth-associated genes in human colon carcinoma cells. J Biol Chem. 1989 May 25;264(15):8922–8927. [PubMed]
  • Chinsky JM, Maa MC, Ramamurthy V, Kellems RE. Adenosine deaminase gene expression. Tissue-dependent regulation of transcriptional elongation. J Biol Chem. 1989 Aug 25;264(24):14561–14565. [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Collart FR, Huberman E. Amplification of the IMP dehydrogenase gene in Chinese hamster cells resistant to mycophenolic acid. Mol Cell Biol. 1987 Sep;7(9):3328–3331. [PMC free article] [PubMed]
  • Collart FR, Huberman E. Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs. J Biol Chem. 1988 Oct 25;263(30):15769–15772. [PubMed]
  • Collart FR, Huberman E. Expression of IMP dehydrogenase in differentiating HL-60 cells. Blood. 1990 Feb 1;75(3):570–576. [PubMed]
  • Darnell JE., Jr Variety in the level of gene control in eukaryotic cells. Nature. 1982 Jun 3;297(5865):365–371. [PubMed]
  • Ebbole DJ, Zalkin H. Cloning and characterization of a 12-gene cluster from Bacillus subtilis encoding nine enzymes for de novo purine nucleotide synthesis. J Biol Chem. 1987 Jun 15;262(17):8274–8287. [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Gudas LJ, Ullman B, Cohen A, Martin DW., Jr Deoxyguanosine toxicity in a mouse T lymphoma: relationship to purine nucleoside phosphorylase-associated immune dysfunction. Cell. 1978 Jul;14(3):531–538. [PubMed]
  • Henderson JF, Lowe JK, Barankiewicz J. Purine and pyrimidine metabolism: pathways, pitfalls and perturbations. Ciba Found Symp. 1977;(48):3–21. [PubMed]
  • Herrmann BG, Frischauf AM. Isolation of genomic DNA. Methods Enzymol. 1987;152:180–183. [PubMed]
  • Homma Y, Henning-Chubb CB, Huberman E. Translocation of protein kinase C in human leukemia cells susceptible or resistant to differentiation induced by phorbol 12-myristate 13-acetate. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7316–7319. [PMC free article] [PubMed]
  • Kazmers IS, Mitchell BS, Dadonna PE, Wotring LL, Townsend LB, Kelley WN. Inhibition of purine nucleoside phosphorylase by 8-aminoguanosine: selective toxicity for T lymphoblasts. Science. 1981 Dec 4;214(4525):1137–1139. [PubMed]
  • Kiguchi K, Collart FR, Henning-Chubb C, Huberman E. Cell differentiation and altered IMP dehydrogenase expression induced in human T-lymphoblastoid leukemia cells by mycophenolic acid and tiazofurin. Exp Cell Res. 1990 Mar;187(1):47–53. [PubMed]
  • Kiguchi K, Collart FR, Henning-Chubb C, Huberman E. Induction of cell differentiation in melanoma cells by inhibitors of IMP dehydrogenase: altered patterns of IMP dehydrogenase expression and activity. Cell Growth Differ. 1990 Jun;1(6):259–270. [PubMed]
  • Lee HJ, Pawlak K, Nguyen BT, Robins RK, Sadée W. Biochemical differences among four inosinate dehydrogenase inhibitors, mycophenolic acid, ribavirin, tiazofurin, and selenazofurin, studied in mouse lymphoma cell culture. Cancer Res. 1985 Nov;45(11 Pt 1):5512–5520. [PubMed]
  • Luskey KL, Faust JR, Chin DJ, Brown MS, Goldstein JL. Amplification of the gene for 3-hydroxy-3-methylglutaryl coenzyme A reductase, but not for the 53-kDa protein, in UT-1 cells. J Biol Chem. 1983 Jul 10;258(13):8462–8469. [PubMed]
  • Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K. Two distinct cDNAs for human IMP dehydrogenase. J Biol Chem. 1990 Mar 25;265(9):5292–5295. [PubMed]
  • Nevins JR. The pathway of eukaryotic mRNA formation. Annu Rev Biochem. 1983;52:441–466. [PubMed]
  • Pall ML. GTP: a central regulator of cellular anabolism. Curr Top Cell Regul. 1985;25:1–20. [PubMed]
  • Pfeuffer T, Helmreich EJ. Structural and functional relationships of guanosine triphosphate binding proteins. Curr Top Cell Regul. 1988;29:129–216. [PubMed]
  • Reeves R, Magnuson NS. Mechanisms regulating transient expression of mammalian cytokine genes and cellular oncogenes. Prog Nucleic Acid Res Mol Biol. 1990;38:241–282. [PubMed]
  • Shapiro DJ, Blume JE, Nielsen DA. Regulation of messenger RNA stability in eukaryotic cells. Bioessays. 1987 May;6(5):221–226. [PubMed]
  • Sidi Y, Mitchell BS. 2'-deoxyguanosine toxicity for B and mature T lymphoid cell lines is mediated by guanine ribonucleotide accumulation. J Clin Invest. 1984 Nov;74(5):1640–1648. [PMC free article] [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Spencer CA, Groudine M. Transcription elongation and eukaryotic gene regulation. Oncogene. 1990 Jun;5(6):777–785. [PubMed]
  • Wilkinson M. A rapid and convenient method for isolation of nuclear, cytoplasmic and total cellular RNA. Nucleic Acids Res. 1988 Nov 25;16(22):10934–10934. [PMC free article] [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...