Regulation of mammalian ornithine decarboxylase

Persson, Lo; El, Wallström; Nasizadeh, Sima; Dartsch, Christine; Jeppsson, Anders; Wendt, Anna; Holmgren, Janna

doi:10.1042/bst0260575

Cited by 20 publications

(12 citation statements)

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“…The removal of these sequences increases the rate of translation of the ODC coding region (16,19,29). However, polyamines do not appear to act through these sequences to regulate ODC translation (39)(40)(41), but some debate on this issue remains (26,35). Our results show that the long 5Ј-UTR of the N. crassa spe-1 mRNA impedes translation of the ODC coding region, although it lacks the obvious secondary structures found in mammalian ODC mRNA (43).…”

Section: Discussionmentioning

confidence: 61%

Polyamine Regulation of Ornithine Decarboxylase Synthesis in Neurospora crassa

Hoyt

Broun

Davis

2000

Molecular and Cellular Biology

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Ornithine decarboxylase (ODC) of the fungus Neurospora crassa, encoded by the spe-1 gene, catalyzes an initial and rate-limiting step in polyamine biosynthesis and is highly regulated by polyamines. In N. crassa, polyamines repress the synthesis and increase the degradation of ODC protein. Changes in the rate of ODC synthesis correlate with similar changes in the abundance of spe-1 mRNA. We identify two sequence elements, one in each of the 5 and 3 regions of the spe-1 gene of N. crassa, required for this polyamine-mediated regulation. A 5 polyamine-responsive region (5 PRR) comprises DNA sequences both in the upstream untranscribed region and in the long 5 untranslated region (5-UTR) of the gene. The 5 PRR is sufficient to confer polyamine regulation to a downstream, heterologous coding region. Use of the ␤-tubulin promoter to drive the expression of various portions of the spe-1 transcribed region revealed a 3 polyamine-responsive region (3 PRR) downstream of the coding region. Neither changes in cellular polyamine status nor deletion of sequences in the 5-UTR alters the half-life of spe-1 mRNA. Sequences in the spe-1 5-UTR also impede the translation of a heterologous coding region, and polyamine starvation partially relieves this impediment. The results show that N. crassa uses a unique combination of polyamine-mediated transcriptional and translational control mechanisms to regulate ODC synthesis.Ornithine decarboxylase (ODC) catalyzes an initial, ratelimiting reaction in the biosynthesis of the polyamines, the conversion of the amino acid ornithine to the divalent polyamine putrescine (1,4-diaminobutane). Putrescine undergoes two subsequent aminopropyl transfer reactions, in which it is converted first to the trivalent spermidine and then to the tetravalent spermine. Polyamines are essential for the growth of normal, and particularly neoplastic, cell types (25, 38), but excess spermidine and spermine are toxic (8,28).ODC is a one of the most highly regulated enzymes of eukaryotic cells, its activity varying over a 100-fold range. ODC activity responds to extracellular signals such as mitogens and growth factors and to changes in the intracellular concentrations of the polyamines themselves. Polyamine regulation of ODC activity is unusual in that the end products do not act as allosteric effectors of this initial enzyme but control only the synthesis and degradation of the ODC protein (reviewed in references 6 and 41).In the filamentous fungus Neurospora crassa, ODC is encoded by the spe-1 gene (3, 9). The regulation of ODC in this fungus resembles that in other eukaryotic organisms. Polyamines reduce the rate of synthesis and increase the rate of degradation of ODC protein (1). However, unlike all other eukaryotes in which polyamine-mediated regulation has been studied, changes in the rate of synthesis ODC in N. crassa are correlated with similar changes (ca. 10-fold) in the abundance of spe-1 mRNA (43). Previously, we identified two regions of the spe-1 gene that affect its expression (27). An upstream ac...

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Section: Discussionmentioning

confidence: 61%

Polyamine Regulation of Ornithine Decarboxylase Synthesis in Neurospora crassa

Hoyt

Broun

Davis

2000

Molecular and Cellular Biology

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“…(B) Levels of Bcl-2 relative to α-tubulin were determined by densitometry analysis of the immunoblotting and statistical results were calculated for at least three independent experiments. * p < 0.05. later than its activity, [33][34][35] indicating that posttranslational regulation play a role in the induction of ODC activity. There are multiple forms of ODC found in various tissues and cells by isoelectric focusing analyses.…”

Section: Discussionmentioning

confidence: 99%

Increasing ornithine decarboxylase activity is another way of prolactin preventing methotrexate-induced apoptosis: Crosstalk between ODC and BCL-2

et al. 2006

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Prolactin has more than 300 separate functions including affecting mammary growth, differentiation, secretion and anti-apoptosis. In the previous studies, prolactin induced Bcl-2 expression to prevent apoptosis and also provoked the activity of ornithine decarboxylase (ODC). Our previous data showed that ODC overexpression upregulates Bcl-2 and prevents tumor necrosis factor alpha (TNF-alpha)- and methotrexate (MTX)-induced apoptosis. Here, we further investigate whether prolactin prevents MTX-induced apoptosis through inducing ODC activity and the relationship between ODC and Bcl-2 upon prolactin stimulation. Prolactin prevented MTX-induced apoptosis in a dose-dependent manner in HL-60 cells. Following prolactin stimulation, ODC enzyme activity also shows an increase in a dose-dependent manner, expressing its maximum level at 3 h, and rapidly declining thereafter. Prolactin-induced ODC activity is completely blocked by a protein kinase C delta (PKCdelta) inhibitor, rottlerin. However, there are no changes in the expressions of ODC mRNA and protein level after prolactin stimulus. It indicates that prolactin may induce ODC activity through the PCKdelta pathway. Besides, Bcl-2 expresses within 1 h of prolactin treatment and this initiating effect of prolactin is not inhibited by alpha-difluoromethylornithine (DFMO). However, Bcl-2 is further enhanced following prolactin stimulation for 4 h and this enhancement is blocked by DFMO. Bcl-2 has no effect on ODC activity and protein levels, but ODC upregulates Bcl-2, which is inhibited by DFMO. Overall, there are two different forms of prolactin effect, it induces Bcl-2 primarily, and following this it stimulates ODC activity. Consequently induced ODC activity further enhances the expression of Bcl-2. The anti-apoptotic effect of prolactin is diminished by DFMO and recovered by putrescine. Obviously, ODC activity is one basis for the anti-apoptotic mechanisms of prolactin. A Bcl-2 inhibitor, HA14-1, together with DFMO, completely blocks the anti-apoptotic effects of prolactin. These results suggest that increasing ODC activity is another way of prolactin preventing MTX-induced apoptosis and that this induction of ODC activity enhances the expression of Bcl-2 strongly enough to bring about the anti-apoptotic function.

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“…Recent studies have shown that ornithine decarboxylase (ODC), a key regulatory enzyme in the biosynthesis of polyamines (putrescine, spermidine, and spermine) is also a protein that, like c-Jun, is essential for mammalian cell proliferation (33)(34)(35)(36)(37) and may have role in cell transformation. Overexpression of ODC alone is sufficient to transform immortalized rodent cell lines (38,39), and, with the ras oncogene, it is able to transform primary cells (40).…”

Section: Introductionmentioning

confidence: 99%