Polyamines and nonmelanoma skin cancer

Gilmour, Susan K.

doi:10.1016/j.taap.2006.11.023

Cited by 74 publications

(53 citation statements)

References 58 publications

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“…ODC has been shown to be both necessary and sufficient for the onset of NMSC in mice and is also elevated in human NMSC (12,14,(53)(54)(55). Thus, the link between ODC and NMSC is indisputable, validating ODC as both a chemoprevention and chemotherapeutic target.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…S-Adenosylmethionine decarboxylase (SAMDC, EC 4.1.4.50) is a rate-limiting enzyme in the biosynthesis of polyamines from putrescine 12 . The samdc gene is widespread in nature and occurs from fungus to yeast.…”

Section: Conclusion:-mentioning

confidence: 99%

Identification and Cloning of S-Adenosylmethionine Decarboxylase (Samdc) Gene From Dictyostelium Discoideum.

Kumar¹,

Sharma²,

Saran³

2018

IJAR

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“…S-Adenosylmethionine was decarboxylated by adenosylmethionine decarboxylase forming S-adenosyl-methylpropylamine (Gilmour, 2007) that subsequently reacts with putrescine forming spermidine by spermidine synthase (Fig. 3).…”

Section: Polyamines Synthesismentioning

confidence: 99%

PLP-Dependent Enzymes: a Potent Therapeutic Approach for Cancer and Cardiovascular Diseases

El-Sayed¹,

Shindia²

2011

Targets in Gene Therapy

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Polyamines and nonmelanoma skin cancer

Cited by 74 publications

References 58 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

Identification and Cloning of S-Adenosylmethionine Decarboxylase (Samdc) Gene From Dictyostelium Discoideum.

PLP-Dependent Enzymes: a Potent Therapeutic Approach for Cancer and Cardiovascular Diseases

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