Feedback regulation of mammalian ornithine decarboxylase

Abstract

Ornithine decarboxylase catalyzes the first step in the biosynthesis of polyamines in mammalian cells. The enzyme is subject to various control mechanisms to maintain adequate intracellular levels of polyamines. Polyamines exert a strong feedback control on ornithine decarboxylase. In a recent study [van Daalen Wetters, T., Macrae, M., Brabant, M., Sittler, A. & Coffino, P. (1989) Mol. Cell. Biol. 9, 5484-54901, it was concluded that feedback control of ornithine decarboxylase is mainly, if not exclusively, a posttranslational phenomenon. The existence of a fast-acting polyamine-stimulated component of ornithine decarboxylase degradation that acts on newly synthesized monomeric forms of the enzyme was postulated. In the present study we have used a transient expression system to test this hypothesis. The expression of ornithine decarboxylase in mock-transfected COS cells varied depending on the cellular supply of polyamines as has been found in other mammalian cells. Thus, supplementing the cells with exogenous spermidine resulted in a marked decrease in ornithine decarboxylase activity, whereas depletion of intracellular polyamines, using an ornithine decarboxylase inhibitor, gave a large increase in the cellular content of the enzyme. COS cells expressing an ornithine decarboxylase mRNA devoid of its 5' non-translated region did not exhibit any feedback control of the enzyme, neither in the presence of exogenous spennidine nor when the intracellular polyamine levels were depleted to the same extent as in the mock-transfected COS cells. The results strongly suggest that the feedback control of ornithine decarboxylase is not merely a posttranslational phenomenon.Cell proliferation is dependent on an adequate supply of the polyamines putrescine, spermidine and spennine [ 1 -31. The first step in the biosynthesis of polyamines is catalyzed by ornithine decarboxylase (ODC), which is regulated by a multitude of mechanisms [4]. Induction of cell growth is often accompanied by an increased transcription of the ODC gene. In many cases the increase in ODC mRNA is much less than the increase observed in ODC activity [5-91. This may partly be explained by a stabilization of the enzyme. However, part of the increase in ODC activity appears to be due to an increase in the efficiency of ODC mRNA translation. Since the turnover of ODC is among the fastest known for a mammalian enzyme [lo], any change in the synthesis or degradation of ODC will rapidly be manifested in a change in the enzyme activity [ll].Polyamines exert a strong feedback control on ODC. A decrease in cellular polyamine content will rapidly cause an increase in the amount of ODC regulation. It has been demonstrated that the turnover of ODC is stimulated when cells are exposed to an excess of extracellular polyamines [17, 181. However, to obtain this effect large quantities of polyamines, often at millimolar concentrations, have to be used. Nevertheless, ODC is downregulated by the addition of micromolar concentrations of polyamines to cells [14,16,17, 191....

Rapid and regulated degradation of ornithine decarboxylase

“…Accordingly, the concept of Coffino and co-workers seems to fit well with the tentative model of ODC degradation (Figure 6). Persson and coworkers recently reported that COS cells overexpressing a transfected ODC transcript devoid of the 5'-untranslated region did not show any polyamine-induced repression under conditions where the mock-transfected cells did [21]. It should be noted, however, that the ODC level in the ODC-transfected cells was 250 times as high as that in the mock-transfected cells and therefore a much higher concentration of polyamine was probably needed to produce enough antizyme for acceleration of ODC decay in these cells.…”

Excess putrescine accumulation inhibits the formation of modified eukaryotic initiation factor 5A (eIF-5A) and induces apoptosis

“…Ornithine decarboxylase (ODC), the first and usually rate-limiting enzyme in polyamine biosynthesis, is a key component in the regulation of cellular polyamine contents. Regulation of ODC itself is a complex combination of control at the level of transcription [4,5], mRNA stability [6,7], translation [8][9][10][11] and in particular protein degradation (reviewed in [12]). This multilevel regulation of ODC has been thought to allow a rapid increase in the enzyme and corresponding cellular polyamine contents in response to mitogenic stimuli.…”

Polyamine metabolism in gliomas

“…Regulation of ODC has been shown to occur on both the transcriptional and translational level [31][32][33][34][35][36]. Shantz and Pegg (1994) have investigated the control of ODC by eukaryotic initiation factors [37].…”