Genetic approaches to the cellular functions of polyamines in mammals

Abstract

The polyamines putrescine, spermidine and spermine are organic cations shown to participate in a bewildering number of cellular reactions, yet their exact functions in intermediary metabolism and specific interactions with cellular components remain largely elusive. Pharmacological interventions have demonstrated convincingly that a steady supply of these compounds is a prerequisite for cell proliferation to occur. The last decade has witnessed the appearance of a substantial number of studies, in which genetic engineering of polyamine metabolism in transgenic rodents has been employed to unravel their cellular functions. Transgenic activation of polyamine biosynthesis through an overexpression of their biosynthetic enzymes has assigned specific roles for these compounds in spermatogenesis, skin physiology, promotion of tumorigenesis and organ hypertrophy as well as neuronal protection. Transgenic activation of polyamine catabolism not only profoundly disturbs polyamine homeostasis in most tissues, but also creates a complex phenotype affecting skin, female fertility, fat depots, pancreatic integrity and regenerative growth. Transgenic expression of ornithine decarboxylase antizyme has suggested that this unique protein may act as a general tumor suppressor. Homozygous deficiency of the key biosynthetic enzymes of the polyamines, ornithine and S-adenosylmethionine decarboxylase, as achieved through targeted disruption of their genes, is not compatible with murine embryogenesis. Finally, the first reports of human diseases apparently caused by mutations or rearrangements of the genes involved in polyamine metabolism have appeared.Keywords: antizyme; ornithine decarboxylase; putrescine; spermidine/spermine N 1 -acetyltransferase; spermidine; spermine; transgenic mouse; transgenic rat. IntroductionThe cellular functions of the natural polyamines (putrescine, spermidine and spermine) are still largely unknown, although a vast number of studies have shown that these polycationic compounds are crucial to the growth and proliferation of mammalian cells. Pharmacological approaches are applied typically in studies aimed to unravel their functions in cellular metabolism and, admittedly, much valuable information has been generated with the use of specific inhibitors of polyamine biosynthesis. However, the last decade has produced a substantial number of experimental studies in which genetic engineering of polyamine metabolism has been used as a tool to elucidate their cellular functions. Studies with genetically engineered mice and rats have not only brought entirely new information about the involvement of polyamines in various physiological and pathophysiological processes but they have likewise challenged some of the conventional wisdoms. Mainly, four different approaches have been applied in the genetic engineering of experimental animals: (a) activation of polyamine biosynthesis through the overexpression of their biosynthetic enzymes; (b) activation of polyamine catabolism through the overexpression of the enzymes i...

Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia

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Rational development of a serum-free medium and fed-batch process for a GS-CHO cell line expressing recombinant antibody

“…These results were consistent with that in screening experiment. Putrescine is one of the polyamines which are cellular constituents shown to be essential for a variety of cell processes related to growth and differentiation, such as DNA replication, transcription and translation (Janne et al 2004). It has been widely utilized as an additive in the development in serum-free media and various literature references have reported its prominent effect on cell growth and protein expression (Jeon et al 2010;Kim et al 2006).…”