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. 1991 Aug;10(8):2119–2124. doi: 10.1002/j.1460-2075.1991.tb07745.x

Gene dosage of CuZnSOD and Down's syndrome: diminished prostaglandin synthesis in human trisomy 21, transfected cells and transgenic mice.

D Minc-Golomb 1, H Knobler 1, Y Groner 1
PMCID: PMC452898  PMID: 1829676

Abstract

Patients with Down's syndrome (DS) exhibit elevated activity of copper zinc superoxide dismutase (CuZnSOD) caused by the trisomy 21 state. To investigate the possible involvement of CuZnSOD gene dosage in perturbation of prostaglandin biosynthesis we analyzed transfected cells and transgenic mice that express elevated levels of human CuZnSOD. It was found that the synthesis of prostaglandin E2 (PGE2) was diminished in transfected PC12-CuZnSOD cells as well as in fibroblasts from DS patients. Primary cells derived from transgenic CuZnSOD mice showed similar reduction. Impaired biosynthesis of prostaglandins was not confined to cells grown in culture since secretion of PGE2 and PGD2 by kidney and cerebellum of transgenic CuZnSOD was significantly lower than in non-transgenic littermate mice. These findings strongly suggest that overexpression of the CuZnSOD gene induces a demotion in PGE2 and PGD2 formation and establish a connection between alteration of prostaglandin biosynthesis in trisomy 21 cells and gene dosage of CuZnSOD.

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Selected References

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

  1. 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]
  2. Avraham K. B., Sugarman H., Rotshenker S., Groner Y. Down's syndrome: morphological remodelling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice. J Neurocytol. 1991 Mar;20(3):208–215. doi: 10.1007/BF01186993. [DOI] [PubMed] [Google Scholar]
  3. Badwey J. A., Karnovsky M. L. Active oxygen species and the functions of phagocytic leukocytes. Annu Rev Biochem. 1980;49:695–726. doi: 10.1146/annurev.bi.49.070180.003403. [DOI] [PubMed] [Google Scholar]
  4. Balazs R., Brooksbank B. W. Neurochemical approaches to the pathogenesis of Down's syndrome. J Ment Defic Res. 1985 Mar;29(Pt 1):1–14. doi: 10.1111/j.1365-2788.1985.tb00302.x. [DOI] [PubMed] [Google Scholar]
  5. Brooksbank B. W., Balazs R. Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down's syndrome fetal brain. Brain Res. 1984 Sep;318(1):37–44. doi: 10.1016/0165-3806(84)90060-9. [DOI] [PubMed] [Google Scholar]
  6. Brooksbank B. W., Martinez M., Balazs R. Altered composition of polyunsaturated fatty acyl groups in phosphoglycerides of Down's syndrome fetal brain. J Neurochem. 1985 Mar;44(3):869–874. doi: 10.1111/j.1471-4159.1985.tb12896.x. [DOI] [PubMed] [Google Scholar]
  7. Cerutti P. A. Prooxidant states and tumor promotion. Science. 1985 Jan 25;227(4685):375–381. doi: 10.1126/science.2981433. [DOI] [PubMed] [Google Scholar]
  8. Conklin B. R., Brann M. R., Buckley N. J., Ma A. L., Bonner T. I., Axelrod J. Stimulation of arachidonic acid release and inhibition of mitogenesis by cloned genes for muscarinic receptor subtypes stably expressed in A9 L cells. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8698–8702. doi: 10.1073/pnas.85.22.8698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cooper D. N., Hall C. Down's syndrome and the molecular biology of chromosome 21. Prog Neurobiol. 1988;30(6):507–530. doi: 10.1016/0301-0082(88)90033-0. [DOI] [PubMed] [Google Scholar]
  10. DeGeorge J. J., Morell P., McCarthy K. D., Lapetina E. G. Cholinergic stimulation of arachidonic acid and phosphatidic acid metabolism in C62B glioma cells. J Biol Chem. 1986 Mar 5;261(7):3428–3433. [PubMed] [Google Scholar]
  11. Egan R. W., Paxton J., Kuehl F. A., Jr Mechanism for irreversible self-deactivation of prostaglandin synthetase. J Biol Chem. 1976 Dec 10;251(23):7329–7335. [PubMed] [Google Scholar]
  12. Elroy-Stein O., Bernstein Y., Groner Y. Overproduction of human Cu/Zn-superoxide dismutase in transfected cells: extenuation of paraquat-mediated cytotoxicity and enhancement of lipid peroxidation. EMBO J. 1986 Mar;5(3):615–622. doi: 10.1002/j.1460-2075.1986.tb04255.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Elroy-Stein O., Groner Y. Impaired neurotransmitter uptake in PC12 cells overexpressing human Cu/Zn-superoxide dismutase--implication for gene dosage effects in Down syndrome. Cell. 1988 Jan 29;52(2):259–267. doi: 10.1016/0092-8674(88)90515-6. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Finazzi-Agró A., Di Giulio A., Amicosante G., Crifó C. Photohemolysis of erythrocytes enriched with superoxide dismutase, catalase and glutathione peroxidase. Photochem Photobiol. 1986 Apr;43(4):409–412. doi: 10.1111/j.1751-1097.1986.tb05622.x. [DOI] [PubMed] [Google Scholar]
  16. Fridovich I. Superoxide dismutases. Adv Enzymol Relat Areas Mol Biol. 1986;58:61–97. doi: 10.1002/9780470123041.ch2. [DOI] [PubMed] [Google Scholar]
  17. Groner Y., Elroy-Stein O., Bernstein Y., Dafni N., Levanon D., Danciger E., Neer A. Molecular genetics of Down's syndrome: overexpression of transfected human Cu/Zn-superoxide dismutase gene and the consequent physiological changes. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):381–393. doi: 10.1101/sqb.1986.051.01.046. [DOI] [PubMed] [Google Scholar]
  18. Groner Y., Lieman-Hurwitz J., Dafni N., Sherman L., Levanon D., Bernstein Y., Danciger E., Elroy-Stein O. Molecular structure and expression of the gene locus on chromosome 21 encoding the Cu/Zn superoxide dismutase and its relevance to Down syndrome. Ann N Y Acad Sci. 1985;450:133–156. doi: 10.1111/j.1749-6632.1985.tb21489.x. [DOI] [PubMed] [Google Scholar]
  19. Hodgson E. K., Fridovich I. The interaction of bovine erythrocyte superoxide dismutase with hydrogen peroxide: chemiluminescence and peroxidation. Biochemistry. 1975 Dec 2;14(24):5299–5303. doi: 10.1021/bi00695a011. [DOI] [PubMed] [Google Scholar]
  20. Iwahashi H., Ishii T., Sugata R., Kido R. Superoxide dismutase enhances the formation of hydroxyl radicals in the reaction of 3-hydroxyanthranilic acid with molecular oxygen. Biochem J. 1988 May 1;251(3):893–899. doi: 10.1042/bj2510893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. LEJEUNE J., GAUTIER M., TURPIN R. Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci. 1959 Mar 16;248(11):1721–1722. [PubMed] [Google Scholar]
  22. Needleman P., Turk J., Jakschik B. A., Morrison A. R., Lefkowith J. B. Arachidonic acid metabolism. Annu Rev Biochem. 1986;55:69–102. doi: 10.1146/annurev.bi.55.070186.000441. [DOI] [PubMed] [Google Scholar]
  23. O'Brien P. J., Hulett L. G. Hydroxyl radical involvement in the luminol chemiluminescence from the reaction of arachidonic acid with sheep vesicular gland microsomes. Prostaglandins. 1980 May;19(5):683–691. doi: 10.1016/0090-6980(80)90167-7. [DOI] [PubMed] [Google Scholar]
  24. Salmon J. A., Flower R. J. Extraction and thin-layer chromatography of arachidonic acid metabolites. Methods Enzymol. 1982;86:477–493. doi: 10.1016/0076-6879(82)86219-8. [DOI] [PubMed] [Google Scholar]
  25. Schickler M., Knobler H., Avraham K. B., Elroy-Stein O., Groner Y. Diminished serotonin uptake in platelets of transgenic mice with increased Cu/Zn-superoxide dismutase activity. EMBO J. 1989 May;8(5):1385–1392. doi: 10.1002/j.1460-2075.1989.tb03519.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Scott M. D., Meshnick S. R., Eaton J. W. Superoxide dismutase-rich bacteria. Paradoxical increase in oxidant toxicity. J Biol Chem. 1987 Mar 15;262(8):3640–3645. [PubMed] [Google Scholar]
  27. Sherman L., Dafni N., Lieman-Hurwitz J., Groner Y. Nucleotide sequence and expression of human chromosome 21-encoded superoxide dismutase mRNA. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5465–5469. doi: 10.1073/pnas.80.18.5465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Whorton A. R., Montgomery M. E., Kent R. S. Effect of hydrogen peroxide on prostaglandin production and cellular integrity in cultured porcine aortic endothelial cells. J Clin Invest. 1985 Jul;76(1):295–302. doi: 10.1172/JCI111960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yarom R., Sapoznikov D., Havivi Y., Avraham K. B., Schickler M., Groner Y. Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down's syndrome. J Neurol Sci. 1988 Dec;88(1-3):41–53. doi: 10.1016/0022-510x(88)90204-3. [DOI] [PubMed] [Google Scholar]
  30. Yim M. B., Chock P. B., Stadtman E. R. Copper, zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5006–5010. doi: 10.1073/pnas.87.13.5006. [DOI] [PMC free article] [PubMed] [Google Scholar]

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