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Gene dosage and down's syndrome: Metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase

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Somatic Cell and Molecular Genetics

Abstract

Down's syndrome (DS) is a human genetic disease caused by triplication of the distal third of chromosome 21 and overexpression of an unknown number of genes residing in it. The gene for the liver-type subunit of phosphofructokinase (PFKL), a key glycolytic enzyme, maps to this region and the product is overproduced in DS erythrocytes and fibroblasts. These facts, together with abnormalities which occur in DS glycolysis, make PFKL overexpression a candidate for causing some aspects of the DS phenotype. A cellular model for examining the consequences of PFKL overexpression in DS was constructed by transfecting rat PC12 cells with the human PFKL cDNA. Phosphofructokinase (PFK) isolated from PFKL-overexpressing clones was more inhibited by ATP and citrate and less activated by fructose-6-phosphate than control PFK; similar results were obtained when PFK preparations from DS and control fibroblasts were compared. In vivo NMR measurements determined that cells overexpressing PFKL performed glycolysis 40% faster than controls. These results show that overexpression of PFKL is the cause for altered biochemical regulatory characteristics of PFK in DS fibroblasts and can result in enhancement of glycolysis rates. It is also shown that increased gene dosage can exert its influence not merely by enhancing the amounts of gene products but also by altering their biochemical nature.

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Literature cited

  1. Hook, E.B. (1981). InTrisomy 21 (Down Syndrome) Research and Perspective (eds.) De La Cruz, F.F., and Gerald, P.S. (University Park Press, Baltimore), pp. 3–68.

    Google Scholar 

  2. Epstein, C.J. (1986a).The Consequences of Chromosome Imbalance—Principles, Mechanisms and Models (Cambridge University Press, Cambridge).

    Google Scholar 

  3. Epstein, C.J. (ed.) (1986b).The Neurobiology of Down Syndrome. (Raven Press, New York).

    Google Scholar 

  4. Summitt, R.L. (1981). InTrisomy 21 (Down Syndrome) Research and Perspective (eds.) De La Cruz, F.F., and Gerald, P.S. (University Park Press, Baltimore), pp. 225–235.

    Google Scholar 

  5. Korenberg, J.R., Kawashima, H., Pulst, S.M., Allen, L., Magenis, E. and Epstein, C. (1990).Am. J. Med. Genet. Suppl. 791–97.

    PubMed  Google Scholar 

  6. Carritt, B., and Litt, M. (1989).Cytogenet. Cell. Genet. 51358–371.

    PubMed  Google Scholar 

  7. Uyeda, K. (1979).Adv. Enzymol. 48193–244.

    PubMed  Google Scholar 

  8. Dunaway, G.A. (1983).Mol. Cell. Biochem. 5275–91.

    PubMed  Google Scholar 

  9. Vora, S. (1982). InCurrent Topics in Biological and Medical Research, Vol. 6 (Alan R. Liss, New York), pp. 119–167.

    Google Scholar 

  10. Vora, S., and Francke, U. (1981).Proc. Natl. Acad. Sci. U.S.A. 78(6):3738–3742.

    PubMed  Google Scholar 

  11. Van Keuren, M., Drabkin, H., Hart, I., Harker, D., Patterson, D., and Vora, S. (1986).Hum. Genet. 7434–40.

    PubMed  Google Scholar 

  12. Cox, D.R., Kawashima, H., Vora, S., and Epstein, C. (1984).Cytogenet. Cell. Genet. 37441–442.

    Google Scholar 

  13. Vora, S., Miranda, A.F., Hernandez, E., and Francke, U. (1983).Hum. Genet. 63374–379.

    PubMed  Google Scholar 

  14. Vora, S., Durham, S., de Martinville, B., George, D.L., and Francke, U. (1982).Somat. Cell Genet. 895–104.

    PubMed  Google Scholar 

  15. Vora, S., Seaman, C., Durham, S., and Piomelli, S. (1980).Proc. Natl. Acad. Sci. U.S.A. 77(1):62–66.

    PubMed  Google Scholar 

  16. Dunaway, G.A., Kasten, T.P., Sebo, T., and Trapp, R. (1988).Biochem. J. 251677–683.

    PubMed  Google Scholar 

  17. Dunaway, G.A., and Kasten, T.P. (1988).Brain Res. 456310–316.

    PubMed  Google Scholar 

  18. Dunaway, G.A., and Kasten, T.P. (1989).Mol. Cell. Biochem. 8771–77.

    PubMed  Google Scholar 

  19. Dunaway, G.A., Kasten, T.P., Crabtree, S., and Mishkar, Y. (1990).Biochem. J. 266823–827.

    PubMed  Google Scholar 

  20. Davidson, M., Collins, M., Byrne, J., and Vora, S. (1983).Biochem. J. 214703–710.

    PubMed  Google Scholar 

  21. Staal, G.E.J., Kalff, A., Heesbeen, E.C., van Veelen, C.W.M., and Rijksen, G. (1987).Cancer Res. 475047–5051.

    PubMed  Google Scholar 

  22. Oskam, R., Rijksen, G., Staal, G.E., and Vora, S. (1985).Cancer Res. 45135–142.

    PubMed  Google Scholar 

  23. Vora, S., Halper, J.P., and Knowles, D.M. (1985).Cancer Res. 452993–3001.

    PubMed  Google Scholar 

  24. Anneren, K.G., Korenberg, J.R., and Epstein, C.J. (1987).Hum. Genet. 7663–65.

    PubMed  Google Scholar 

  25. Magnani, M., Stocchi, V., Novelli, G., Dacha, M., and Forniani, G. (1987).Clin. Physiol. Biochem. 59–14.

    PubMed  Google Scholar 

  26. Lapidot, A., Gopher, A., Korman, S.H., and Mandel, H. (1990). Ninth Annual Scientific Meeting of the Society of Magnetic Resonance in Medicine, New York (abstract).

  27. Horwitz, B., Schapiro, M.B., Grady, C.L., and Rapoport, S.I. (1990).J. Ment. Def. Res. 34237–252.

    Google Scholar 

  28. Groner, Y., Elroy-Stein, O., Avraham, K.B., Yarom, R., Schikler, M., Knobler, H., and Rotman, G. (1990).J. Physiol. 8453–77.

    Google Scholar 

  29. Elroy-Stein, O., and Groner, Y. (1988).Cell 52259–267.

    PubMed  Google Scholar 

  30. Minc-Golomb, D., Knobler, H., and Groner, Y. (1991).Embo J. 10(8):2119–2124.

    PubMed  Google Scholar 

  31. Avraham, K.B., Schikler, M., Sapoznikov, D., Yarom, R., and Groner, Y. (1988).Cell 54823–829.

    PubMed  Google Scholar 

  32. Avraham, K.B., Sugarman, H., Rotshenker, S., and Groner, Y. (1991).J. Neurocytol. 20208–215.

    PubMed  Google Scholar 

  33. Schikler, M., Knobler, H., Avraham, K.B., Elroy-Stein, O., and Groner, Y. (1989).EMBO J. 8(5):1385–1392.

    PubMed  Google Scholar 

  34. Levanon, D., Danciger, E., Dafni, N., Bernstein, Y., Elson, A., Moens, W., Brandeis, M., and Groner, Y. (1989).DNA 8(10):733–743.

    PubMed  Google Scholar 

  35. Elson, A., Levanon, D., Brandeis, M., Dafni, N., Bernstein, Y., Danciger, E., and Groner, Y. (1990).Genomics 747–56.

    PubMed  Google Scholar 

  36. Lee, F., Mulligan, R., Berg, P., and Ringold, G.Nature 294:228–231.

  37. Ausubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.E., Smith, J.A., and Struhl, K. (1989).Current Protocols in Molecular Biology (John Wiley & Sons, New York).

    Google Scholar 

  38. Chomczynski, P., and Sacchi, N. (1987).Anal. Biochem. 162156–159.

    PubMed  Google Scholar 

  39. Weil, J., and Epstein, C.J. (1979).Hum. Genet. 31478–488.

    Google Scholar 

  40. Mosmann, T. (1983).J. Immunol. Methods 6555–63.

    PubMed  Google Scholar 

  41. Kasten, T.P., Naqui, D., Kruep, D., and Dunaway, G.A. (1983).Biochem. Biophys. Res. Commun. 111(2):462–469.

    PubMed  Google Scholar 

  42. Dunaway, G.A., and Kasten, T.P. (1985).J. Biol. Chem. 260(7):4180–4185.

    PubMed  Google Scholar 

  43. Bradford, M.M. (1976).Anal. Biochem. 72248–254.

    PubMed  Google Scholar 

  44. Towbin, H., Staehelin, T., and Gordon, J. (1979).Proc. Natl. Acad. Sci. U.S.A. 76(9):4350–4354.

    PubMed  Google Scholar 

  45. Neeman, M., and Degani, H. (1989).Cancer Res. 49589–594.

    PubMed  Google Scholar 

  46. Neeman, M., Rushkin, E., Kadouri, A., and Degani, H. (1988).Mag. Res. Med. 7236–242.

    Google Scholar 

  47. Mulligan, R.C., and Berg, P. (1980).Science 2091422–1427.

    PubMed  Google Scholar 

  48. Southern, P.J., and Berg, P. (1982).J. Mol. Appl. Genet. 1327–341.

    PubMed  Google Scholar 

  49. Greene, L.A., and Tischler, A.S. (1976).Proc. Natl. Acad. Sci. U.S.A. 73(7):2424–2428.

    PubMed  Google Scholar 

  50. Felgner, P.L., Gadek, T.R., Holm, M., Roman, R., Chan, H.W., Wenz, M., Northrop, J.P., Ringold, G.M., and Danielsen, M. (1987).Proc. Natl. Acad. Sci. U.S.A. 847413–7417.

    PubMed  Google Scholar 

  51. Saiki, R.K., Gelfand, D.H., Stoffel, S., Scharf, S.J., Higuchi, R., Horn, G.T., Mullis, K.B., and Erlich, H.A. (1988).Science 239487–491.

    PubMed  Google Scholar 

  52. Lundberg, P., Harmsen, E., Ho, C., and Vogel, H.J. (1990).Anal. Biochem. 191193–222.

    PubMed  Google Scholar 

  53. Sharma, P.M., Reddy, G.R., Vora, S., Babior, B.M., and McLachlan, A. (1989).Gene 77177–183.

    PubMed  Google Scholar 

  54. Gonzalez, F., and Kemp, R.G. (1978).J. Biol. Chem. 253(5):1493–1497.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Genetics and Virology, The Weizmann Institute of Science, Rehovot, Israel

    Ari Elson, Yael Bernstein, Ditsa Levanon & Yoram Groner

  2. Department of Chemical Physics, The Weizmann Institute of Science, Rehovot, Israel

    Hadassa Degani

  3. Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel

    Herzl Ben-Hur

Authors
  1. Ari Elson
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  2. Yael Bernstein
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  3. Hadassa Degani
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  4. Ditsa Levanon
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  5. Herzl Ben-Hur
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  6. Yoram Groner
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Elson, A., Bernstein, Y., Degani, H. et al. Gene dosage and down's syndrome: Metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase. Somat Cell Mol Genet 18, 143–161 (1992). https://doi.org/10.1007/BF01233161

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  • DOI: https://doi.org/10.1007/BF01233161

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