The Two-Step Model of Prostaglandin Signal Termination: In Vitro Reconstitution with the Prostaglandin Transporter and Prostaglandin 15 Dehydrogenase

Nomura, Teruhisa; Lu, Run; Pucci, Michael L.; Schuster, Victor L.

doi:10.1124/mol.65.4.973

Cited by 132 publications

(113 citation statements)

References 32 publications

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“…CREB pathway leading to enhanced CYP19 transcription and increased aromatase activity (10). Extracellular PGE 2 can be transported via PGT into the cell, where it is inactivated by cytosolic 15-PGDH (24). Here, we show that changes in the levels of PGT modulate extracellular levels of PGE 2 , which lead, in turn, to changes in CYP19 transcription and aromatase activity.…”

Section: A B C D E F G H Discussionmentioning

confidence: 81%

“…This transporter is a member of the organic anion superfamily of transporting polypeptides that contain 12-transmembrane spanning domains (22). PGT is rate limiting in the delivery of PGE 2 to cytosolic 15-PGDH, which results in its oxidation and inactivation (23,24). Although numerous studies have shown the significance of enzymes involved in the synthesis and catabolism of PGE 2 as determinants of CYP19 transcription and aromatase activity, the potential importance of PGT in regulating aromatase expression is unknown.…”

Section: Introductionmentioning

confidence: 99%

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The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Subbaramaiah

Hudis

Dannenberg

2011

Cancer Prevention Research

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Cytochrome P450 aromatase, encoded by the CYP19 gene, catalyzes estrogen synthesis. In obese postmenopausal women, increased estrogen synthesis in adipose tissue has been linked to hormonedependent breast carcinogenesis. Hence, it is important to elucidate the mechanisms that regulate CYP19 gene expression. Prostaglandin E 2 (PGE 2 ) stimulates the cyclic AMP (cAMP) ! protein kinase A (PKA) ! cAMP responsive element binding protein (CREB) pathway leading to increased CYP19 transcription. The prostaglandin transporter (PGT) removes PGE 2 from the extracellular milieu and delivers it to the cytosol, where it is inactivated. The main objective of this study was to determine whether PGT regulates CYP19 transcription. Silencing of PGT in preadipocytes increased PGE 2 levels in the extracellular medium, thereby stimulating the cAMP ! PKA pathway resulting in enhanced interaction between pCREB, p300, and the CYP19 I.3/II promoter. A reciprocal decrease in the interaction between the CYP19 I.3/II promoter and BRCA1, a repressor of CYP19 transcription, was observed. Overexpressing PGT reduced extracellular PGE 2 levels, suppressed the cAMP ! PKA pathway, enhanced the interaction between BRCA1 and p300, and inhibited aromatase expression. We also compared the PGT ! aromatase axis in preadipocytes versus adipocytes. Aromatase levels were markedly increased in preadipocytes versus adipocytes. This increase in aromatase was explained, at least in part, by reduced PGT levels leading to enhanced PGE 2 ! cAMP ! PKA signaling. In addition to regulating aromatase expression, PGT-mediated changes in extracellular PGE 2 levels were a determinant of adipocyte differentiation. Collectively, these results suggest that PGT modulates adipogenesis and thereby PGE 2 -mediated activation of the cAMP ! PKA ! CREB pathway leading to altered CYP19 transcription and aromatase activity.

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Section: A B C D E F G H Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Subbaramaiah

Hudis

Dannenberg

2011

Cancer Prevention Research

View full text Add to dashboard Cite

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“…PGT mediates PGE 2 cellular uptake, which can be driven by an exchange of organic anions such as lactate . PGT-mediated PGE 2 uptake from the extracellular environment is an initial step for degradation of PGE 2 by 15-hydroxy PG dehydrogenase (PGDH) in the cytoplasm (Nomura et al 2004). Expression of PGT may be coordinately regulated with COXs (Bao et al 2002).…”

Section: Introductionmentioning

confidence: 99%

A role of prostaglandin transporter in regulating PGE2 release from human bronchial epithelial BEAS-2B cells in response to LPS

Shirasaka

Shichiri

Kasai

et al. 2013

Journal of Endocrinology

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Naturally occurring prostaglandin E 2 (PGE 2 ) plays a role in inflammatory responses through eicosanoid signaling pathways. PGE 2 is impermeable to cell membranes at physiological pH and needs solute carrier across the membranes; however, it remains unclear how intercellular concentrations of PGE 2 are regulated under the condition of inflammation. We aimed to clarify a role of organic anion-transporting polypeptide 2A1 (OATP2A1/SLCO2A1), also known as prostaglandin transporter (PGT), in PGE 2 release from cells. Human bronchial epithelial BEAS-2B cells were treated with lipopolysaccharide (LPS), and PGT inhibitors were tested to evaluate contribution of PGT to PGE 2 release by assessing its extracellular concentration and characterizing PGT-mediated PGE 2 efflux in Xenopus laevis oocytes. As a result, LPS elevated mRNA expression of a pro-inflammatory cytokine IL6 and extracellular concentration of PGE 2 in human bronchial epithelial BEAS-2B cells. PGT inhibitors tested (e.g. bromocresol green (BCG), bromosulfophthalein (BSP), and PGB 1 ) significantly inhibited efflux of PGE 2 from oocytes expressing PGT. Similarly, the amount of released PGE 2 from the BEAS-2B cells decreased in the presence of BCG and BSP by 45 and 44% respectively while TGBz increased the concentration by 71%, suggesting that PGT mediates the release. In conclusion, these results imply a role of PGT in regulating intra-and extracellular concentrations of PGE 2 in response to cells under inflammatory conditions.

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“…Inactivation of PGE 2 located in the tumor microenvironment has been suggested to occur by a two-step model (13). The first step is mediated by the prostaglandin transporter (PGT), which engages carrier-mediated membrane transport of prostaglandins, including PGE 2 , PGF 2α , and PGD 2 (14), from the extracellular milieu to the cytoplasm.…”

mentioning

confidence: 99%

“…This transporter belongs to the organic anion superfamily of transporting polypeptides that contain 12-transmembrane spanning domains and are coordinately regulated with COXs (15,16). The second step of PGE 2 inactivation occurs in the cytoplasm, where 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catabolizes and thus inactivates PGE 2 (13,16). We have recently reported that the expression and activity of 15-PGDH is repressed in human colorectal cancers and Apc min mouse adenomas, resulting in decreased catabolism of PGE 2 (17,18).…”

mentioning

confidence: 99%

Regulation of Prostaglandin Transporters in Colorectal Neoplasia

Holla

Backlund

Yang³

et al. 2008

Cancer Prevention Research

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Prostaglandin E 2 (PGE 2 ) promotes cancer progression by affecting cell proliferation, apoptosis, angiogenesis, and the immune response. It has been reported that PGE 2 is transported or passes through the cell membrane via prostaglandin-specific transporters including the prostaglandin transporter (PGT, an influx transporter) and the multidrug resistance-associated protein 4 (an efflux transporter). PGT can facilitate the removal of PGE 2 from the extracellular milieu by transporting it into the cell, where 15-hydroxyprostaglandin dehydrogenase (15-PGDH) then oxidizes PGE 2 into 15-keto PGE 2 . We previously reported that 15-PGDH expression is reduced in most colorectal cancers, indicating the tumor suppressor role of this gene. In the present study, we show that PGT expression is also decreased (whereas multidrug resistance-associated protein 4 expression is elevated) in human colorectal cancer specimens (compared with expression in normal mucosa) and in colorectal cancer cell lines. Furthermore, we found that PGT expression decreased in premalignant adenomas in Apc min mice and was partially restored (in human colorectal cancer cell lines) by treatment with a DNA demethylating agent or histone deacetylase inhibitor. Forced PGT overexpression in vitro reduced extracellular PGE 2 levels and increased intracellular levels of its catabolic product 15-keto PGE 2 . Our data suggest that the existing model to explain increased PGE 2 in colorectal neoplasia should be modified to include the novel mechanism of coordinated up-and down-regulation of genes involved in PGE 2 transport.

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The Two-Step Model of Prostaglandin Signal Termination: In Vitro Reconstitution with the Prostaglandin Transporter and Prostaglandin 15 Dehydrogenase

Cited by 132 publications

References 32 publications

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

A role of prostaglandin transporter in regulating PGE2 release from human bronchial epithelial BEAS-2B cells in response to LPS

Regulation of Prostaglandin Transporters in Colorectal Neoplasia

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