Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1994 Apr 15;299(Pt 2):409–415. doi: 10.1042/bj2990409

Overexpression of liver-type phosphofructokinase (PFKL) in transgenic-PFKL mice: implication for gene dosage in trisomy 21.

A Elson 1, D Levanon 1, Y Weiss 1, Y Groner 1
PMCID: PMC1138287  PMID: 8172601

Abstract

The human liver-type subunit of the key glycolytic enzyme, phosphofructokinase (PFKL), is encoded by a gene residing on chromosome 21. This chromosome, when triplicated, causes the phenotypic expression of Down's syndrome (trisomy 21). Increased phosphofructokinase activity, a result of gene dosage, is commonly found in erythrocytes and fibroblasts from Down's syndrome patients. We describe the construction of transgenic mice overexpressing PFKL for use as a well-defined model system, in which the effects of PFKL overexpression in various tissues, and throughout development, can be studied. Mice transgenic for a murine PFKL 'gene cDNA' hybrid construct were found to overexpress PFKL in a tissue-specific manner resembling that of the endogenous enzyme. Although unchanged in adult brain, PFK specific activity was found to have been almost doubled in brains of embryonic transgenic-PFKL mice, suggesting that the extra copies of the PFKL gene are expressed during the developmental period. This pattern of overexpression of PFKL in brains of transgenic-PFKL mice suggests that gene-dosage effects may be temporally separated from some of their consequences, adding an additional layer of complexity to the analysis of gene dosage in trisomy 21.

Full text

PDF
409

Images in this article

412Figure 2
on p.412
413Figure 3
on p.413

Selected References

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

  1. Annerén K. G., Korenberg J. R., Epstein C. J. Phosphofructokinase activity in fibroblasts aneuploid for chromosome 21. Hum Genet. 1987 May;76(1):63–65. doi: 10.1007/BF00283052. [DOI] [PubMed] [Google Scholar]
  2. Avraham K. B., Schickler M., Sapoznikov D., Yarom R., Groner Y. Down's syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase. Cell. 1988 Sep 9;54(6):823–829. doi: 10.1016/s0092-8674(88)91153-1. [DOI] [PubMed] [Google Scholar]
  3. Bradford M. M. 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. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  4. Dunaway G. A. A review of animal phosphofructokinase isozymes with an emphasis on their physiological role. Mol Cell Biochem. 1983;52(1):75–91. doi: 10.1007/BF00230589. [DOI] [PubMed] [Google Scholar]
  5. Dunaway G. A., Kasten T. P., Crabtree S., Mhaskar Y. Age-related changes in subunit composition and regulation of hepatic 6-phosphofructo-1-kinase. Biochem J. 1990 Mar 15;266(3):823–827. [PMC free article] [PubMed] [Google Scholar]
  6. Dunaway G. A., Kasten T. P., Kolm P. Alteration of 6-phosphofructo-1-kinase isozyme pools during heart development and aging. J Biol Chem. 1986 Dec 25;261(36):17170–17173. [PubMed] [Google Scholar]
  7. Dunaway G. A., Kasten T. P. Physiological implications of the alteration of 6-phosphofructo-1-kinase isozyme pools during brain development and aging. Brain Res. 1988 Jul 26;456(2):310–316. doi: 10.1016/0006-8993(88)90233-8. [DOI] [PubMed] [Google Scholar]
  8. Dunaway G. A., Kasten T. P. Physiological relevance of the changing subunit composition and regulatory properties of the 6-phosphofructo-1-kinase isozyme pools during heart and muscle development. Mol Cell Biochem. 1989 May 4;87(1):71–77. doi: 10.1007/BF00421084. [DOI] [PubMed] [Google Scholar]
  9. Dunaway G. A., Kasten T. P., Sebo T., Trapp R. Analysis of the phosphofructokinase subunits and isoenzymes in human tissues. Biochem J. 1988 May 1;251(3):677–683. doi: 10.1042/bj2510677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Elson A., Bernstein Y., Degani H., Levanon D., Ben-Hur H., Groner Y. Gene dosage and Down's syndrome: metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase. Somat Cell Mol Genet. 1992 Mar;18(2):143–161. doi: 10.1007/BF01233161. [DOI] [PubMed] [Google Scholar]
  11. Epstein C. J., Avraham K. B., Lovett M., Smith S., Elroy-Stein O., Rotman G., Bry C., Groner Y. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8044–8048. doi: 10.1073/pnas.84.22.8044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Epstein C. J., Epstein L. B., Cox D. R., Weil J. Functional implications of gene dosage effects in trisomy 21. Hum Genet Suppl. 1981;2:155–172. doi: 10.1007/978-3-642-68006-9_12. [DOI] [PubMed] [Google Scholar]
  13. Gehnrich S. C., Gekakis N., Sul H. S. Liver (B-type) phosphofructokinase mRNA. Cloning, structure, and expression. J Biol Chem. 1988 Aug 25;263(24):11755–11759. [PubMed] [Google Scholar]
  14. Holtzman D. M., Bayney R. M., Li Y. W., Khosrovi H., Berger C. N., Epstein C. J., Mobley W. C. Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome. EMBO J. 1992 Feb;11(2):619–627. doi: 10.1002/j.1460-2075.1992.tb05094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Levanon D., Danciger E., Dafni N., Bernstein Y., Elson A., Moens W., Brandeis M., Groner Y. The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK. DNA. 1989 Dec;8(10):733–743. doi: 10.1089/dna.1989.8.733. [DOI] [PubMed] [Google Scholar]
  16. Meienhofer M. C., Lagrange J. L., Cottreau D., Lenoir G., Dreyfus J. C., Kahn A. Phosphofructokinase in human blood cells. Blood. 1979 Aug;54(2):389–400. [PubMed] [Google Scholar]
  17. Palmiter R. D., Sandgren E. P., Avarbock M. R., Allen D. D., Brinster R. L. Heterologous introns can enhance expression of transgenes in mice. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):478–482. doi: 10.1073/pnas.88.2.478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rongnoparut P., Verdon C. P., Gehnrich S. C., Sul H. S. Isolation and characterization of the transcriptionally regulated mouse liver (B-type) phosphofructokinase gene and its promoter. J Biol Chem. 1991 May 5;266(13):8086–8091. [PubMed] [Google Scholar]
  19. Uyeda K. Phosphofructokinase. Adv Enzymol Relat Areas Mol Biol. 1979;48:193–244. doi: 10.1002/9780470122938.ch4. [DOI] [PubMed] [Google Scholar]
  20. Van Keuren M., Drabkin H., Hart I., Harker D., Patterson D., Vora S. Regional assignment of human liver-type 6-phosphofructokinase to chromosome 21q22.3 by using somatic cell hybrids and a monoclonal anti-L antibody. Hum Genet. 1986 Sep;74(1):34–40. doi: 10.1007/BF00278782. [DOI] [PubMed] [Google Scholar]
  21. Vora S., Francke U. Assignment of the human gene for liver-type 6-phosphofructokinase isozyme (PFKL) to chromosome 21 by using somatic cell hybrids and monoclonal anti-L antibody. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3738–3742. doi: 10.1073/pnas.78.6.3738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Vora S. Isozymes of phosphofructokinase. Isozymes Curr Top Biol Med Res. 1982;6:119–167. [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES