Abstract
We have generated a transgenic mouse line harbouring the human ornithine decarboxylase gene under the control of mouse metallothionein I promoter. Even in the absence of an exposure to heavy metals, ornithine decarboxylase was over-expressed in heart, testis, brain, and especially in liver, of the transgenic animals. An exposure of the transgenic mice to zinc further enhanced the enzyme activity to a level which in liver represented up to 8000-fold increase in comparison with non-transgenic animals. The striking stimulation of liver ornithine decarboxylase activity upon treatment of the transgenic mice with zinc was accompanied by a nearly 150-fold increase in the hepatic putrescine content as compared with similarly treated non-transgenic animals. Even though the liver putrescine concentration reached that of spermidine and spermine in the transgenic animals, the contents of the higher polyamines only transiently increased upon zinc administration and then returned to the basal level. These findings once again indicate that mammalian cells possess extremely powerful regulatory machinery to prevent an over-accumulation of spermidine and spermine in non-dividing cells, and that very high tissue putrescine concentrations can be tolerated, at least for periods of a few days, with seemingly no phenotypic changes.
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Selected References
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- Habener J. F., Cwikel B. J., Hermann H., Hammer R. E., Palmiter R. D., Brinster R. L. Metallothionein-vasopressin fusion gene expression in transgenic mice. Nephrogenic diabetes insipidus and brain transcripts localized to magnocellular neurons. J Biol Chem. 1989 Nov 5;264(31):18844–18852. [PubMed] [Google Scholar]
- Hakovirta H., Keiski A., Toppari J., Halmekytö M., Alhonen L., Jänne J., Parvinen M. Polyamines and regulation of spermatogenesis: selective stimulation of late spermatogonia in transgenic mice overexpressing the human ornithine decarboxylase gene. Mol Endocrinol. 1993 Nov;7(11):1430–1436. doi: 10.1210/mend.7.11.8114757. [DOI] [PubMed] [Google Scholar]
- Halmekytö M., Alhonen L., Alakuijala L., Jänne J. Transgenic mice over-producing putrescine in their tissues do not convert the diamine into higher polyamines. Biochem J. 1993 Apr 15;291(Pt 2):505–508. doi: 10.1042/bj2910505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Halmekytö M., Hyttinen J. M., Sinervirta R., Utriainen M., Myöhänen S., Voipio H. M., Wahlfors J., Syrjänen S., Syrjänen K., Alhonen L. Transgenic mice aberrantly expressing human ornithine decarboxylase gene. J Biol Chem. 1991 Oct 15;266(29):19746–19751. [PubMed] [Google Scholar]
- Hickok N. J., Wahlfors J., Crozat A., Halmekytö M., Alhonen L., Jänne J., Jänne O. A. Human ornithine decarboxylase-encoding loci: nucleotide sequence of the expressed gene and characterization of a pseudogene. Gene. 1990 Sep 14;93(2):257–263. doi: 10.1016/0378-1119(90)90233-h. [DOI] [PubMed] [Google Scholar]
- Hyvönen T., Keinänen T. A., Khomutov A. R., Khomutov R. M., Eloranta T. O. Monitoring of the uptake and metabolism of aminooxy analogues of polyamines in cultured cells by high-performance liquid chromatography. J Chromatogr. 1992 Feb 7;574(1):17–21. doi: 10.1016/0378-4347(92)80093-6. [DOI] [PubMed] [Google Scholar]
- Jänne J., Williams-Ashman H. G. On the purification of L-ornithine decarboxylase from rat prostate and effects of thiol compounds on the enzyme. J Biol Chem. 1971 Mar 25;246(6):1725–1732. [PubMed] [Google Scholar]
- Kauppinen L., Myöhänen S., Halmekytö M., Alhonen L., Jänne J. Transgenic mice over-expressing the human spermidine synthase gene. Biochem J. 1993 Jul 15;293(Pt 2):513–516. doi: 10.1042/bj2930513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Orian J. M., Tamakoshi K., Mackay I. R., Brandon M. R. New murine model for hepatocellular carcinoma: transgenic mice expressing metallothionein-ovine growth hormone fusion gene. J Natl Cancer Inst. 1990 Mar 7;82(5):393–398. doi: 10.1093/jnci/82.5.393. [DOI] [PubMed] [Google Scholar]
- Sasaki H., Nakazato M., Saraiva M. J., Matsuo H., Sakaki Y. Activity of a metallothionein-transthyretin fusion gene in transgenic mice. Possible effect of plasmid sequences on tissue-specific expression. Mol Biol Med. 1989 Aug;6(4):345–353. [PubMed] [Google Scholar]
- Searle P. F., Davison B. L., Stuart G. W., Wilkie T. M., Norstedt G., Palmiter R. D. Regulation, linkage, and sequence of mouse metallothionein I and II genes. Mol Cell Biol. 1984 Jul;4(7):1221–1230. doi: 10.1128/mcb.4.7.1221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seiler N., Daune G., Bolkenius F. N., Knödgen B. Ornithine aminotransferase activity, tissue ornithine concentrations and polyamine metabolism. Int J Biochem. 1989;21(4):425–432. doi: 10.1016/0020-711x(89)90367-4. [DOI] [PubMed] [Google Scholar]
- Shanahan C. M., Rigby N. W., Murray J. D., Marshall J. T., Townrow C. A., Nancarrow C. D., Ward K. A. Regulation of expression of a sheep metallothionein 1a-sheep growth hormone fusion gene in transgenic mice. Mol Cell Biol. 1989 Dec;9(12):5473–5479. doi: 10.1128/mcb.9.12.5473. [DOI] [PMC free article] [PubMed] [Google Scholar]