A negative regulatory element within the proximal promoter region of the rat ornithine decarboxylase gene

Zhao, Biwei; Kumar, Addanki P.; Butler, Andrew C.

doi:10.1002/1098-2744(200012)29:4<212::aid-mc1003>3.0.co;2-0

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…Because of their charge, polyamines are able to bind to RNA, DNA, and proteins and thereby influence gene expression (4). Both polyamine content and ODC enzyme activity are tightly regulated in cells, and ODC is induced in response to a variety of proliferative stimuli by alterations in its transcription, translation, and protein degradation (5)(6)(7)(8)(9)(10). A link between neoplastic transformation and increased ODC enzyme activity, as well as increases in intracellular putrescine and spermidine, have been well documented in animal models of skin carcinogenesis and other epithelial tumors (11)(12)(13)(14)(15)(16)(17).…”

supporting

confidence: 87%

Cytoplasmic Accumulation of the RNA-binding Protein HuR Stabilizes the Ornithine Decarboxylase Transcript in a Murine Nonmelanoma Skin Cancer Model

Nowotarski

Shantz

2010

Journal of Biological Chemistry

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Ornithine decarboxylase (ODC) is the first and usually ratelimiting enzyme in the polyamine biosynthetic pathway. Under normal physiological conditions, polyamine content and ODC enzyme activity are highly regulated. However, the induction of ODC activity is an early step in neoplastic transformation. The studies described here use normal mouse keratinocytes (C5N cells), and spindle carcinoma cells (A5 cells) to explore the regulation of ODC in nonmelanoma skin cancer development. Previous results have shown that induction of ODC activity is both necessary and sufficient for the promotion of skin tumors. We see a marked increase in ODC enzyme activity in A5 cells compared with C5N keratinocytes, which correlates with a 4-fold stabilization of ODC mRNA. These data suggest that ODC is post-transcriptionally regulated in skin tumor development. Thus, we sought to investigate whether the ODC transcript interacts with the RNA-binding protein HuR, which is known to bind to and stabilize its target mRNAs. We show that HuR is able to bind to the ODC 3-UTR in A5 cells but not in C5N cells. Immunofluorescence results reveal that HuR is present in both the nucleus and cytoplasm of A5 cells, whereas C5N cells exhibit strictly nuclear localization of HuR. Knockdown experiments in A5 cells showed that when HuR is depleted, ODC RNA becomes less stable, and ODC enzyme activity decreases. Together, these data support the hypothesis that HuR plays a causative role in ODC up-regulation during nonmelanoma skin cancer development by binding to and stabilizing the ODC transcript. Ornithine decarboxylase (ODC)2 catalyzes the conversion of the amino acid ornithine to the diamine putrescine, which is subsequently converted to the higher polyamines spermidine and spermine (1, 2). Polyamines are small, ubiquitous polycations and are necessary for normal cell growth and development. Thus, the ablation of ODC is lethal in utero (3). Because of their charge, polyamines are able to bind to RNA, DNA, and proteins and thereby influence gene expression (4). Both polyamine content and ODC enzyme activity are tightly regulated in cells, and ODC is induced in response to a variety of proliferative stimuli by alterations in its transcription, translation, and protein degradation (5-10). A link between neoplastic transformation and increased ODC enzyme activity, as well as increases in intracellular putrescine and spermidine, have been well documented in animal models of skin carcinogenesis and other epithelial tumors (11-17). Moreover, a link between human nonmelanoma skin cancer (NMSC), the most prevalent cancer in the United States, and elevated ODC enzyme activity levels has been described (18). The induction of ODC activity during tumor development has been attributed to both increased Odc gene transcription and translation of the ODC mRNA (9, 19).Interestingly, changes in intracellular polyamine pools have also been shown to affect the localization of RNA-binding proteins (RBPs), which influence the stability of their target mRNA transcripts (2...

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confidence: 87%

Cytoplasmic Accumulation of the RNA-binding Protein HuR Stabilizes the Ornithine Decarboxylase Transcript in a Murine Nonmelanoma Skin Cancer Model

Nowotarski

Shantz

2010

Journal of Biological Chemistry

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“…Regulation of ODC expression is complex and dependent on both transcriptional and posttranscriptional pathways. Endogenous mitogen, and phorbol ester‐induced expression of ODC is dependent on interactions of transcription factors with multiple cis ‐elements in the ODC promoter [29–42]. For example, the c‐ myc oncoprotein‐induced ODC expression and c‐ myc /max heterodimers specifically interact with E‐box sequences located in the first intron of the rat ODC gene [34].…”

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confidence: 99%

Estrogen‐dependent regulation of ornithine decarboxylase in breast cancer cells through activation of nongenomic cAMP‐dependent pathways

Qin

Samudio²,

Ngwenya

et al. 2004

Molecular Carcinogenesis

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17beta-estradiol (E2) induces ornithine decarboxylase (ODC) activity in several E2-responsive tissues/cells, and this study investigated the mechanism of hormone-induced transactivation in MCF-7 human breast cancer cells. E2-induced reporter gene (luciferase) activity in MCF-7 cells transfected with a construct (pODC1) containing the -164 to +29 region of the human ODC gene promoter linked to bacterial luciferase. This promoter sequence contains GC-rich Sp1 binding sites, CAAT, LSF, cAMP response element (CRE), and TATA motifs. Deletion and mutational analysis of the ODC promoter showed that both CAAT and LSF sites were required for hormone-induced transactivation. Gel mobility shift and DNA footprinting assays indicated that NFYA and LSF bound the CAAT and LSF motifs, respectively, and GAL4-NFYA/GAL4-LSF chimeras were also activated by E2, 8-bromo-cAMP, and protein kinase A (PKA) expression plasmid. However, E2-induced transactivation of GAL4-NFYA and GAL4-LSF was blocked by the PKA inhibitor SQ22356 indicating that the mechanism of ODC induction by E2 involves upregulation of cAMP/PKA through nongenomic pathways of estrogen action.

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A negative regulatory element within the proximal promoter region of the rat ornithine decarboxylase gene

Cited by 2 publications

References 25 publications

Cytoplasmic Accumulation of the RNA-binding Protein HuR Stabilizes the Ornithine Decarboxylase Transcript in a Murine Nonmelanoma Skin Cancer Model

Cytoplasmic Accumulation of the RNA-binding Protein HuR Stabilizes the Ornithine Decarboxylase Transcript in a Murine Nonmelanoma Skin Cancer Model

Estrogen‐dependent regulation of ornithine decarboxylase in breast cancer cells through activation of nongenomic cAMP‐dependent pathways

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