Characterization of a transgenic mouse line over-expressing the human ornithine decarboxylase gene

Halmekytö, Maria; Alhonen, Leena; Wahlfors, Jarmo; Sinervirta, Riitta; Eloranta, Terho O.; Jänne, Juhani

doi:10.1042/bj2780895

Cited by 60 publications

(70 citation statements)

References 18 publications

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“…It is well known that polyamine metabolism is highly dynamic and subject to compensatory responses designed to conserve intracellular polyamine pools (13,19,28,29,41,42). Thus, as seen here and elsewhere (13, 28), activation of polyamine catabolism at the level of SSAT gives rise to a compensatory increase in polyamine biosynthetic enzymes (i.e., ODC and SAMDC).…”

Section: Discussionmentioning

confidence: 76%

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Tucker

Murphy²,

Kisiel³

et al. 2005

Cancer Research

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Intracellular polyamine pools are homeostatically maintained by processes involving biosynthesis, catabolism, and transport. Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N 1 -acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model. Herein, we examined the effects of differential SSAT expression on intestinal tumorigenesis in the Apc Min/+ (MIN) mouse. When MIN mice were crossed with SSAT-overproducing transgenic mice, they developed 3-and 6-fold more adenomas in the small intestine and colon, respectively, than normal MIN mice. Despite accumulation of the SSAT product, N 1 -acetylspermidine, spermidine and spermine pools were only slightly decreased due to a huge compensatory increase in polyamine biosynthetic enzyme activities that gave rise to enhanced metabolic flux. When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype. Despite the loss in catabolic capability, tumor spermidine and spermine pools failed to increase significantly due to a compensatory decrease in biosynthetic enzyme activity giving rise to a reduced metabolic flux. Loss of heterozygosity at the Apc locus was observed in tumors from both SSAT-transgenic and -deficient MIN mice, indicating that loss of heterozygosity remained the predominant oncogenic mechanism. Based on these data, we propose a model in which SSAT expression alters flux through the polyamine pathway giving rise to metabolic events that promote tumorigenesis. The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers. (Cancer Res 2005; 65(12): 5390-8)

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Section: Discussionmentioning

confidence: 76%

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Tucker

Murphy²,

Kisiel³

et al. 2005

Cancer Research

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“…It should be noted that in the only transgenic ODC model that developed skin tumors after chemical carcinogen initiation, the ODC transgene is a C-terminal truncated copy (Megosh et al 1995), which could no longer be degraded by the endogenous antizyme. We have chosen to use the full human ODC gene because in an earlier study the full human ODC including its promoter has been used as the transgene to achieve overexpression in most mouse tissues (Halmekyto et al 1991). We reasoned that because the ODC used was of human origin, it may be able to escape the mouse antizyme control without C-terminal truncation.…”

Section: Discussionmentioning

confidence: 99%

Ornithine Decarboxylase (ODC) Expression Pattern in Human Prostate Tissues and ODC Transgenic Mice

Young

Salomon

et al. 2006

J Histochem Cytochem.

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(PR) S U M M A R Y Ornithine decarboxylase (ODC) is the key enzyme in the polyamine synthesis pathway and is overexpressed in a variety of cancers. We have performed a detailed immunostaining analysis of the expression of ODC in normal, benign prostatic hyperplasia (BPH), and cancerous prostate tissues. We conclude that ODC is overexpressed in both BPH and neoplastic tissues and that ODC overexpression appears to be an early event in prostate carcinogenesis. The extent of overexpression decreases as cancer progresses. Interestingly, ODC overexpression was also detected in patients who underwent androgen ablation therapy, suggesting ODC overexpression may contribute to the androgenindependent survival of prostate cancer cells. ODC is perinuclear localized in BPH samples but is diffusely cytoplasmic in cancer samples. Having shown ODC overexpression in human prostate cancer, we developed prostate-specific ODC transgenic mice to further investigate whether ODC overexpression alone is a causal factor in prostate carcinogenesis. RT-PCR and immunostaining confirmed that ODC was overexpressed in a subset of prostate epithelial cells. Although minor nucleoli enlargements in some tissues were detected, gross morphological changes were not observed in transgenic prostates. Therefore, overexpression of ODC alone in this subset of prostate epithelial cells is not sufficient to induce prostate carcinogenesis. (J Histochem Cytochem 54:223-229, 2006)

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“…8). Despite disruption of synthetic pathways, changes in intracellular spermine levels are difficult to observe because of multilevel homeostatic mechanisms controlling spermine concentrations (Porter et al, 1990;Halmekyto et al, 1991;Fogel-Petrovic et al, 1996;Hayashi et al, 1996;Pietila et al, 1997;Morrison et al, 1998;Kepka-Lenhart et al, 2000;Suppola et al, 2001). SSAT, the enzyme that catalyzes the back-conversion of spermine to N-acetyl forms, is tightly regulated by intracellular spermine.…”

Section: Polyamine Regulationmentioning

confidence: 99%

Disrupted Spermine Homeostasis: A Novel Mechanism in Polyglutamine-Mediated Aggregation and Cell Death

Colton¹,

Xu²,

Burke³

et al. 2004

J. Neurosci.

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Characterization of a transgenic mouse line over-expressing the human ornithine decarboxylase gene

Cited by 60 publications

References 18 publications

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Ornithine Decarboxylase (ODC) Expression Pattern in Human Prostate Tissues and ODC Transgenic Mice

Disrupted Spermine Homeostasis: A Novel Mechanism in Polyglutamine-Mediated Aggregation and Cell Death

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