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J. Biol. Chem., Vol. 277, Issue 28, 25323-25328, July 12, 2002

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Targeted Disruption of Spermidine/Spermine N¹-Acetyltransferase Gene in Mouse Embryonic Stem Cells
EFFECTS ON POLYAMINE HOMEOSTASIS AND SENSITIVITY TO POLYAMINE ANALOGUES^*

Kirsi Niiranen, Marko Pietilä, Terhi J. Pirttilä, Aki Järvinen, Maria Halmekytö, Veli-Pekka Korhonen, Tuomo A. Keinänen, Leena Alhonen, and Juhani Jänne^§

From the A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P. O. Box 1627, FIN-70211 Kuopio, Finland

We have generated mouse embryonic stem cells with targeted disruption of spermidine/spermine N¹-acetyltransferase (SSAT) gene. The targeted cells did not contain any inducible SSAT activity, and the SSAT protein was not present. The SSAT-deficient cells proliferated normally and appeared to maintain otherwise similar polyamine pools as did the wild-type cells, with the possible exception of constantly elevated (about 30%) cellular spermidine. As expected, the mutated cells were significantly more resistant toward the growth-inhibitory action of polyamine analogues, such as N¹,N¹¹-diethylnorspermine. However, this resistance was not directly attributable to cellular depletion of the higher polyamines spermidine and spermine, as the analogue depleted the polyamine pools almost equally effectively in both wild-type and SSAT-deficient cells. Tracer experiments with [C¹⁴]-labeled spermidine revealed that SSAT activity is essential for the back-conversion of spermidine to putrescine as radioactive N¹-acetylspermidine and putrescine were readily detectable in N¹,N¹¹-diethylnorspermine-exposed wild-type cells but not in SSAT-deficient cells. Similar experiments with [C¹⁴]spermine indicated that the latter polyamine was converted to spermidine in both cell lines and, unexpectedly, more effectively in the targeted cells than in the parental cells. This back-conversion was only partly inhibited by MDL72527, an inhibitor of polyamine oxidase. These results indicated that SSAT does not play a major role in the maintenance of polyamine homeostasis, and the toxicity exerted by polyamine analogues is largely not based on SSAT-induced depletion of the natural polyamines. Moreover, embryonic stem cells appear to operate an SSAT-independent system for the back-conversion of spermine to spermidine.

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