Transgenic mice overexpressing ornithine and S-adenosylmethionine decarboxylases maintain a physiological polyamine homoeostasis in their tissues

Abstract

Recent work has shown that transgenic mice overexpressing human ornithine decarboxylase display no marked changes in the tissue concentrations of spermidine or spermine in spite of a dramatic increase in putrescine levels. In the tissues of transgenic mice carrying the human spermidine synthase gene and in those of hybrid mice overexpressing both ornithine decarboxylase and spermidine synthase, spermidine and spermine levels remain within normal limits. To test whether the amount of the propylamine group donor, decarboxylated S-adenosylmethionine, limits the conversion of putrescine into the higher polyamines, we have produced transgenic mouse lines harbouring the rat S-adenosylmethionine decarboxylase gene in their genome. However, neither these mice nor the hybrid mice overexpressing both ornithine decarboxylase and S-adenosylmethionine decarboxylase displayed significant changes in their spermidine and spermine tissue levels. To study the mechanism by which cells maintain the constancy of the polyamine concentrations, we have determined the metabolic flux of polyamines in transgenic primary fibroblasts using pulse labelling. The results indicate that the polyamine flow is faster in transgenic primary fibroblasts than in non-transgenic fibroblasts and that the intracellular homoeostasis of higher polyamines is maintained at least partly by the acetylation of spermidine and spermine and their secretion into the medium.

Mathematical Modeling of Polyamine Metabolism in Mammals

“…4) predict a very remarkable buffering of the levels of higher polyamines, in agreement with available experimental data (49,77). However, we only observed such a tendency when we extended the core system model to consider the production of SAM from methionine.…”

“…As it happens with ODC, SAMdc knock-outs are lethal at the earliest stages of embryonic development (76). SAMdcoverexpressing mice show modest inductions (5-fold increase) (49), with only small changes of higher polyamine levels. In a recently published work, Ͼ100-fold inductions have been obtained with little variation of polyamine content (77).…”

“…However, a cross-breeding of ODC-and SAMdc-overexpressing transgenic mice shows that putrescine is not limiting in polyamine synthesis, and those mice still maintain a polyamine homeostasis. Heljasvaara et al (49) suggest that, since polyamine accumulation is toxic, a homeostasis is not unexpected. Indeed, they proved that this homeostasis is reached by an increased rate of the bi-cycle, with a faster polyamine synthesis followed by an increase of acetylated polyamine efflux, although they could not find any direct evidence of increased SSAT activity (49).…”

Polyamines and apoptosis

“…The regulation of cellular polyamine concentrations is sophisticated and thorough [3,4]. In cells major polyamine concentrations changes are physiologically unlikely, except for Put, the product of the highly inducible and rapidly turning over ODC It should however be remembered that Put concentrations are usually lower than those of Spd and Spm by more than an order of magnitude.…”

“…antizymes) ensures rapid adaptation to physiological needs in situations of changing environmental and metabolic conditions. Owing to their efficient regulation even the overexpression of ODC and AdoMetDC in mice allows the maintenance of polyamine homeostasis in tissues [4].…”