Overexpression of spermidine/spermine N-1-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

We recently generated a transgenic mouse line overexpressing spermidine/spe rmine N-1-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 li ne overexpressing the SSAT gene under the control of a heavy-metal-inducibl e mouse metallothionein I (MT) promoter. Even in the absence of heavy metal s, changes in the tissue polyamine pools indicated that a marked activation of polyamine catabolism had occurred in the transgenic animals. As with th e SSAT transgenic mice generated previously, the mice of the new line (MT-S SAT) suffered permanent hair loss, but this occurred considerably later tha n in the previous SSAT transgenic animals. Liver was the most affected tiss ue in the MT-SSAT transgenic animals, revealed by putrescine overaccumulati on, significant decrease in spermidine concentration and >90 % reduction in the spermine pool. Even though hepatic SSAT mRNA accumulated to massive le vels in non-induced transgenic animals, SSAT activity was only moderately e levated. Administration of ZnSO4 further elevated the level of hepatic SSAT message and induced enzyme activity, but not more than 2- to 3-fold. Treat ment of the transgenic animals with the polyamine analogue N-1,N-11-diethyl norspermine (DENSPM) resulted in an immense induction, more than 40 000-fol d, 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. T he treatment also resulted in a marked mortality (up to 60 %) among the tra nsgenic animals which showed ultrastructural changes in the liver, most not ably mitochondrial swelling, one of the earliest signs of cell injury. Thes e results indicated that, even without its own promoter, SSAT is powerfully induced by the polyamine analogue through a mechanism that appears to invo lve a direct translational and/or heterogenous nuclear RNA processing contr ol. It is likewise significant that overexpression of SSAT renders the anim als extremely sensitive to polyamine analogues.