We recently generated a transgenic mouse line overexpressing spermidine/spermine N1-acetyltransferase (SSAT) gene under its own promoter. The tissue polyamine pools of these animals were profoundly affected and the mice were hairless from early age. We have now generated another transgenic-mouse line overexpressing the SSAT gene under the control of a heavy-metal-inducible mouse metallothionein I (MT) promoter. Even in the absence of heavy metals, changes in the tissue polyamine pools indicated that a marked activation of polyamine catabolism had occurred in the transgenic animals. As with the SSAT transgenic mice generated previously, the mice of the new line (MT-SSAT) suffered permanent hair loss, but this occurred considerably later than in the previous SSAT transgenic animals. Liver was the most affected tissue in the MT–SSAT transgenic animals, revealed by putrescine overaccumulation, significant decrease in spermidine concentration and > 90% reduction in the spermine pool. Even though hepatic SSAT mRNA accumulated to massive levels in non-induced transgenic animals, SSAT activity was only moderately elevated. Administration of ZnSO4 further elevated the level of hepatic SSAT message and induced enzyme activity, but not more than 2- to 3-fold. Treatment of the transgenic animals with the polyamine analogue N1,N11-diethylnorspermine (DENSPM) resulted in an immense induction, more than 40000-fold, of enzyme activity in the liver of transgenic animals, and minor changes in the SSAT mRNA level. Liver spermidine and spermine pools were virtually depleted within 1–2 days in response to the treatment with the analogue. The treatment also resulted in a marked mortality (up to 60%) among the transgenic animals which showed ultrastructural changes in the liver, most notably mitochondrial swelling, one of the earliest signs of cell injury. These results indicated that, even without its own promoter, SSAT is powerfully induced by the polyamine analogue through a mechanism that appears to involve a direct translational and/or heterogenous nuclear RNA processing control. It is likewise significant that overexpression of SSAT renders the animals extremely sensitive to polyamine analogues.
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March 1999
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Research Article|
February 22 1999
Overexpression of spermidine/spermine N1-acetyltransferase under the control of mouse metallothionein I promoter in transgenic mice: evidence for a striking post-transcriptional regulation of transgene expression by a polyamine analogue
Suvikki SUPPOLA;
Suvikki SUPPOLA
*A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland
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Marko PIETILÄ;
Marko PIETILÄ
*A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland
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Jyrki J. PARKKINEN;
Jyrki J. PARKKINEN
*A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland
†Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland
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Veli-Pekka KORHONEN;
Veli-Pekka KORHONEN
*A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland
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Leena ALHONEN;
Leena ALHONEN
*A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland
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Maria HALMEKYTÖ;
Maria HALMEKYTÖ
‡Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, U.S.A.
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Carl W. PORTER;
Carl W. PORTER
‡Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, U.S.A.
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Juhani JÄNNE
Juhani JÄNNE
1
*A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland
1To whom correspondence should be addressed (e-mail Juhani.Janne@uku.fi).
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Publisher: Portland Press Ltd
Received:
August 21 1998
Revision Received:
October 12 1998
Accepted:
December 10 1998
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1999
1999
Biochem J (1999) 338 (2): 311–316.
Article history
Received:
August 21 1998
Revision Received:
October 12 1998
Accepted:
December 10 1998
Citation
Suvikki SUPPOLA, Marko PIETILÄ, Jyrki J. PARKKINEN, Veli-Pekka KORHONEN, Leena ALHONEN, Maria HALMEKYTÖ, Carl W. PORTER, Juhani JÄNNE; Overexpression of spermidine/spermine N1-acetyltransferase under the control of mouse metallothionein I promoter in transgenic mice: evidence for a striking post-transcriptional regulation of transgene expression by a polyamine analogue. Biochem J 1 March 1999; 338 (2): 311–316. doi: https://doi.org/10.1042/bj3380311
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