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

Bettuzzi, Saverio; Davalli, Pierpaola; Astancolle, Serenella; Pinna, Cristina; Roncaglia, R; Boraldi, Federica; Tiozzo, Roberta; Sharrard, M; Corti, Angelo

doi:10.1016/s0014-5793(99)00182-9

Cited by 57 publications

(43 citation statements)

References 27 publications

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“…7,28 This relationship is also observed in skeletal muscle, where ODC is upregulated by the androgen receptor, promoting cell proliferation and delayed differentiation, both of which are features of tumor formation. 29 Even though some authors have reported how polyamine pathway controls cell cycle, 30 ODC functional contribution in prostate tumor initiation has not been fully explored to date.…”

Section: Discussionmentioning

confidence: 99%

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Shukla–Dave

Castillo-Martín

Chen

et al. 2016

The American Journal of Pathology

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Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well-characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODCoverexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN. (Am J Pathol 2016, 186: 3131e3145; http://dx

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Section: Discussionmentioning

confidence: 99%

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Shukla–Dave

Castillo-Martín

Chen

et al. 2016

The American Journal of Pathology

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“…Studies from several laboratories have shown that perturbation of the levels of antizyme, ODC, or polyamines can affect cell cycle progression (9,14,27,28). However, the mechanisms by which antizyme may influence the cell cycle have remained unclear.…”

Section: Discussionmentioning

confidence: 99%

Antizyme Targets Cyclin D1 for Degradation

Newman

Mobascher

Mangold

et al. 2004

Journal of Biological Chemistry

128

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Overproduction of the ornithine decarboxylase (ODC) regulatory protein ODC-antizyme has been shown to correlate with cell growth inhibition in a variety of different cell types. Although the exact mechanism of this growth inhibition is not known, it has been attributed to the effect of antizyme on polyamine metabolism. Antizyme binds directly to ODC, targeting ODC for ubiquitin-independent degradation by the 26 S proteasome. We now show that antizyme induction also leads to degradation of the cell cycle regulatory protein cyclin D1. We demonstrate that antizyme is capable of specific, noncovalent association with cyclin D1 and that this interaction accelerates cyclin D1 degradation in vitro in the presence of only antizyme, cyclin D1, purified 26 S proteasomes, and ATP. In vivo, antizyme up-regulation induced either by the polyamine spermine or by antizyme overexpression causes reduction of intracellular cyclin D1 levels. The antizyme-mediated pathway for cyclin D1 degradation is independent of the previously characterized phosphorylation-and ubiquitination-dependent pathway, because antizyme up-regulation induces the degradation of a cyclin D1 mutant (T286A) that abrogates its ubiquitination. We propose that antizyme-mediated degradation of cyclin D1 by the proteasome may provide an explanation for the repression of cell growth following antizyme up-regulation. The regulatory protein antizyme (AZ)1 has been studied primarily in the context of its role in facilitating degradation of the enzyme ornithine decarboxylase (ODC), which catalyzes the rate-limiting step in polyamine synthesis (reviewed in Refs. 1-3). AZ is therefore thought to be dedicated principally to the feedback regulation of polyamine levels. AZ synthesis is controlled via an unusual mechanism of translational frameshifting. The ribosomal frameshift required for the translation of full-length AZ is directly induced by polyamines when their levels rise (4, 5). Polyamines can thus inhibit their own synthesis via AZ-mediated down-regulation of ODC. This mechanism serves to prevent extreme fluctuations in polyamine levels, which are thought to be toxic (6 -8). Despite this homeostatic mechanism, the levels of polyamines and ODC vary markedly during the cell cycle, indicating that additional factors control polyamine levels and suggesting a role for this pathway in the regulation of cell proliferation (9).Overproduction of AZ in a variety of cell types, including malignant oral keratinocytes, hepatoma cell lines, and prostate cancer cells, coincides with growth inhibition (10 -12) and cell cycle arrest in the G 1 phase (13,14). Furthermore, overexpression of antizyme in both mouse skin cancer and gastric epithelia models has been shown to result in tumor suppression (15,16). These and other observations of antiproliferative effects of antizyme prompted us to test whether antizyme may have a specific role in cell cycle regulation, thereby accounting for its potential role as a tumor suppressor.The cell cycle arrest previously seen in prostate carcinoma ...

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“…This fact and the proven importance of ODC in cell transformation could suggest that putrescine could serve not only as a requested substrate for spermidine (and spermine) synthesis but also as a regulatory signal of cell proliferation. It has been shown that peaks of putrescine occur in different phases of the cell cycle (29,75). Furthermore, putrescine stimulates tyrosine phosphorylation by tyrosine kinases and the expression of the nuclear oncogenes c-fos and c-jun (35).…”

Section: Model Predicts Compensatory Mechanisms To Keep Polyamine Hommentioning

confidence: 99%

Mathematical Modeling of Polyamine Metabolism in Mammals

Rodríguez‐Caso

Montañez

Cascante

et al. 2006

Journal of Biological Chemistry

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Polyamines are considered as essential compounds in living cells, since they are involved in cell proliferation, transcription, and translation processes. Furthermore, polyamine homeostasis is necessary to cell survival, and its deregulation is involved in relevant processes, such as cancer and neurodegenerative disorders. Great efforts have been made to elucidate the nature of polyamine homeostasis, giving rise to relevant information concerning the behavior of the different components of polyamine metabolism, and a great amount of information has been generated. However, a complex regulation at transcriptional, translational, and metabolic levels as well as the strong relationship between polyamines and essential cell processes make it difficult to discriminate the role of polyamine regulation itself from the whole cell response when an experimental approach is given in vivo. To overcome this limitation, a bottom-up approach to model mathematically metabolic pathways could allow us to elucidate the systemic behavior from individual kinetic and molecular properties. In this paper, we propose a mathematical model of polyamine metabolism from kinetic constants and both metabolite and enzyme levels extracted from bibliographic sources. This model captures the tendencies observed in transgenic mice for the so-called key enzymes of polyamine metabolism, ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermine spermidine N-acetyl transferase. Furthermore, the model shows a relevant role of S-adenosylmethionine and acetyl-CoA availability in polyamine homeostasis, which are not usually considered in systemic experimental studies.During much of the last century, biology was an attempt to reduce biological phenomena to the behavior of molecules. Despite the enormous success of this approach, most biological functions arise from interactions among many components, yielding nonlinear behavior that has been fine tuned by natural selection to achieve specific functional properties (1, 2). Therefore, a comprehensive understanding of biological functions requires a new systemic perspective. In the last few years, systems biology and synthetic biology have emerged to fulfill this goal (3-5). Systems biology approaches are hypothesis-driven and involve iterative rounds of model building, prediction, experimentation, and model refinement and development (6, 7). Computer science development is allowing faster and faster numerical simulations of mathematical models. Interesting and relevant mathematical models of several well known metabolic pathways have been published very recently (8 -10). Far from replacing knowledge acquisition from experimental evidence, mathematical modeling allows to test and define more accurately hypothesis that have to be experimentally tested later. Furthermore, modeling allows to build a comprehensive framework based on a compilation of the experimental data provided by the scientific community. With this philosophy, we propose and study a mathematical model of polyamine metabolism. We...

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

Cited by 57 publications

References 27 publications

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Antizyme Targets Cyclin D1 for Degradation

Mathematical Modeling of Polyamine Metabolism in Mammals

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