Cell cycle phase‐dependent induction of ornithine decarboxylase‐antizyme

Linden, Margareta; Anehus, Siw; Långström, Eva; Baldetorp, Bo; Heby, Olle

doi:10.1002/jcp.1041250215

Cited by 15 publications

(8 citation statements)

References 20 publications

(35 reference statements)

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“…3b), drops markedly at 12 h, when the ODC mRNA reaches its highest level, and increases again to maximal values from mid S phase (24 h) onward, when the ODC transcript is at its lowest concentration. Similar results were obtained by others when detecting the OAZ activity in Ehrlich ascites tumor cells [28]. This suggests that when growing ¢broblasts approach the restriction point at late G I , unknown factors may come into play triggering temporarily the repression of the OAZ gene and the simultaneous induction of the ODC gene, leading to the peaks of polyamine accumulation (Fig.…”

Section: Discussionsupporting

confidence: 87%

Coordinate changes of polyamine metabolism regulatory proteins during the cell cycle of normal human dermal fibroblasts

et al. 1999

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In human dermal fibroblasts, brought to quiescence (G H ) by serum starvation, the S phase peaked 24 h and G P /M phases 36 h after serum re-addition. Under the same conditions, ornithine decarboxylase mRNA peaked at 12 h, decreased markedly in S phase and remained low until 48 h. Conversely, ornithine decarboxylase antizyme transcript dropped to its lowest level at 12 h, while reaching its highest values between 24 and 48 h. Ornithine decarboxylase activity followed essentially the pattern of its mRNA, but relative changes were much greater. S-Adenosylmethionine decarboxylase transcript and enzyme activity also peaked at around 12 h, decreasing thereafter. Spermidine/spermine N I -acetyltransferase mRNA and activity reached the highest values at 36^48 h. Putrescine concentration increased up to 18 h and fell dramatically in the S phase, remaining low thereafter. Both spermidine and spermine reached peaks at 18 h and decreased in the S phase, but not nearly as much as putrescine. We discuss how this comprehensive study may help to understand the involvement of polyamines in the control of cell proliferation.z 1999 Federation of European Biochemical Societies.

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Section: Discussionsupporting

confidence: 87%

Coordinate changes of polyamine metabolism regulatory proteins during the cell cycle of normal human dermal fibroblasts

et al. 1999

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“…Polyamines are required components for both protein and nucleic acid synthesis, and polyamine biosynthesis is regulated throughout the course of the cell cycle (26,27). Antizyme, through its ability to suppress both the polyamine biosynthetic enzyme ODC and polyamine transporters, is an effective endogenous mechanism for limiting intracellular polyamine levels.…”

Section: Discussionmentioning

confidence: 99%

Agmatine Suppresses Proliferation by Frameshift Induction of Antizyme and Attenuation of Cellular Polyamine Levels

Satriano¹,

Matsufuji²,

Murakami³

et al. 1998

Journal of Biological Chemistry

134

113

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Polyamines are required for entry and progression of the cell cycle. As such, augmentation of polyamine levels is essential for cellular transformation. Polyamines are autoregulated through induction of antizyme, which represses both the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase and cellular polyamine transport. In the present study we demonstrate that agmatine, a metabolite of arginine via arginine decarboxylase (an arginine pathway distinct from that of the classical polyamines), also serves the dual regulatory functions of suppressing polyamine biosynthesis and cellular polyamine uptake through induction of antizyme. The capacity of agmatine to induce antizyme is demonstrated by: (a) an agmatine-dependent translational frameshift of antizyme mRNA to produce a fulllength protein and (b) suppression of agmatine-dependent inhibitory activity by either anti-antizyme IgG or antizyme inhibitor. Furthermore, agmatine administration depletes intracellular polyamine levels to suppress cellular proliferation in a transformed cell line. This suppression is reversible with polyamine supplementation. We propose a novel regulatory pathway in which agmatine acts as an antiproliferative molecule and potential tumor suppressor by restricting the cellular polyamine supply required to support growth.Polyamines (putrescine, spermidine, and spermine) are required for DNA replication, proliferation, and cell homeostasis (1-3). Ornithine decarboxylase (ODC) 1 is the first rate-limiting enzyme of polyamine biosynthesis and one of the most highly regulated eukaryotic enzymes. Cellular polyamine transporters are stimulated by many of the same factors that induce ODC activity, and similarly, enhanced cellular polyamine uptake occurs both in normal but rapidly proliferating cells (4) and in tumor cell lines (5-8). Cells in vivo can acquire polyamines released into the circulation by other cells, dietary sources, and gut flora. Polyamines have been demonstrated to play an important role in the transformation process. Conversely, polyamine depletion results in growth arrest (9, 10).Intracellular polyamine concentrations are autoregulated by the induction of the protein antizyme (11). Antizyme is the only known endogenous protein that binds to ODC, inhibiting activity and accelerating its degradation (12). In addition to inhibiting polyamine biosynthesis, antizyme has recently been shown to concurrently suppress polyamine transporter(s) (13,14). Pharmacological inhibition of ODC activity, however, has been shown to result in compensatory cellular polyamine uptake (6). Beneficial therapeutic intervention must therefore address both polyamine transport as well as biosynthesis (for review see Ref. 15).The metabolism of arginine to agmatine by ADC has only recently been demonstrated in mammals (16). As agmatine and polyamines are structurally analogous polycationic molecules derived from distinct arginine-dependent pathways (6), we speculated that the ADC metabolite agmatine may play a role in regulating intracellul...

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“…Ornithine decarboxylase antizyme (ODC-Az) is a polyamine inducible inhibitory protein of ODC activity (Linden et al, 1985). ODC-Az downregulates ODC activity by ODC degradation (Li and Cono, 1994).…”

Section: Introductionmentioning

confidence: 99%

Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme

et al. 2001

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The hamster ornithine decarboxylase antizyme (ODCAz) cDNA was transfected into the hamster malignant oral keratinocyte cell line, HCPC-1. Ectopic expression of ODC-Az resulted in the reversion of malignant phenotypes and alteration of DNA methylation status of CCGG sites. The phenotypes examined include ODC enzymatic activity, doubling time, morphological change, anchorage dependent growth, tumorigenicity in nude mice, induction of epithelial dierentiation marker protein (involucrin), and change of cell cycle position. Comparison of CCGG DNA methylation status of the ODC-Az and control vector transfectants revealed a signi®cant increase in demethylation of 5-methyl cytosines (m 5 C) of CCGG sites in the ODC-Az transfectants. Ectopic expression of ODC-Az gene in hamster malignant oral keratinocytes led to reduce ODC activity and the subsequent demethylation of 5-methyl cytosines, presumably via the ODC/ polyamines/ decarboxylated S-adenosylmethionine (dc-AdoMet) pathways. Our data suggest that ODC-Az shared the same pathway of polyamines/ dc-AdoMet/DNA methyltransferase (DNA MTase). We propose that ODC-Az mediates a novel mechanism in tumor suppression by DNA demethylation and presumably re-activation of key cellular genes silenced by DNA hypermethylation during cancer development. Oncogene (2001) 20, 24 ± 33.

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Cell cycle phase‐dependent induction of ornithine decarboxylase‐antizyme

Cited by 15 publications

References 20 publications

Coordinate changes of polyamine metabolism regulatory proteins during the cell cycle of normal human dermal fibroblasts

Coordinate changes of polyamine metabolism regulatory proteins during the cell cycle of normal human dermal fibroblasts

Agmatine Suppresses Proliferation by Frameshift Induction of Antizyme and Attenuation of Cellular Polyamine Levels

Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme

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