EP2 and EP4 prostanoid receptor signaling

Regan, John W.

doi:10.1016/j.lfs.2003.09.031

Cited by 401 publications

(413 citation statements)

References 36 publications

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“…Furthermore, we showed that L-161,982 could block CREB phosphorylation at Ser 133. It is well documented that PGE 2 via EP2 and EP4 receptors can increase intracellular cAMP levels, which acts as a second messenger molecule and leads to PKA activation and robust serine phosphorylation of CREB [13]. However, in our studies, we did not observe increased intracellular cAMP levels in HCA-7 cells in response to PGE 2 (data not shown).…”

Section: Discussioncontrasting

confidence: 78%

“…The EP1 receptors are coupled to Gα q protein and are known to increase cytosolic Ca 2+ levels in response to PGE 2 . Both EP2 and EP4 receptors are coupled to Gα s and can increase formation of intracellular cyclic AMP (cAMP) by activating adenylyl cyclase, whereas Gα i -coupled EP3 receptors inhibit cAMP formation [13]. Significant reduction of AOM-induced colonic aberrant crypt foci (ACFs) were observed in mice with homozygous deletions in EP1, EP2 and EP4 receptors, but not EP3 [15,37,38].…”

Section: Discussionmentioning

confidence: 99%

“…The effects of PGE 2 are mediated by four G protein-coupled receptors called the EP 1-4 [13]. We first characterized the expression of the prostaglandin receptors.…”

Section: Ep4 Receptor Mediates Pge 2 -Induced Phosphorylation Of Erksmentioning

confidence: 99%

“…PGE 2 signals are transduced via four G-protein coupled cell surface receptors, termed as EP1, EP2, EP3, and EP4 receptors. The EP1 receptors are coupled to Gα q protein and are known to increase cytosolic Ca 2+ levels in response to PGE 2 [13]. Both EP2 and EP4 receptors are coupled to Gα s and can increase formation of intracellular cyclic AMP (cAMP) by activating adenylyl cyclase, whereas Gα i -coupled EP3 receptors inhibit cAMP formation [13].…”

Section: Introductionmentioning

confidence: 99%

“…The EP1 receptors are coupled to Gα q protein and are known to increase cytosolic Ca 2+ levels in response to PGE 2 [13]. Both EP2 and EP4 receptors are coupled to Gα s and can increase formation of intracellular cyclic AMP (cAMP) by activating adenylyl cyclase, whereas Gα i -coupled EP3 receptors inhibit cAMP formation [13]. Thus, the effects of PGE 2 on cell proliferation appear to be mediated by its overall second messenger response, which in turn depends on receptor-ligand affinity and ligand concentration [14].…”

Section: Introductionmentioning

confidence: 99%

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The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

Cherukuri

Chen

Goulet

et al. 2007

Experimental Cell Research

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Accumulating evidence indicates that elevated levels of prostaglandin E 2 (PGE 2 ) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE 2 exerts its effects through four G-protein coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE 2 to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE 2 -induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE 2 induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE 2 treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE 2 driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE 2 in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer.

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Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

“…The effects of PGE 2 are mediated by four G protein-coupled receptors called the EP 1-4 [13]. We first characterized the expression of the prostaglandin receptors.…”

Section: Ep4 Receptor Mediates Pge 2 -Induced Phosphorylation Of Erksmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

Cherukuri

Chen

Goulet

et al. 2007

Experimental Cell Research

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The Gαs‐protein‐mediated pathway may be steadily stimulated by prostanoid EP2 receptors, but not by EP4 receptors

et al. 2022

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EP2 and EP4 prostanoid receptors have long been considered to have similar roles, since they are known to couple with Gαs‐protein and activate cAMP‐mediated signaling pathways. In this study, we re‐evaluated the results of cAMP assays with or without phosphodiesterase (PDE) inhibitor pretreatment. Here, we show that in the absence of PDE inhibitor pretreatment, prostaglandin E2 causes accumulation of cAMP in EP2 receptors, whereas markedly low levels of cAMP accumulated in EP4 receptors. By applying the Black/Leff operational model calculation, we found that EP2 receptors have a biased ability to intrinsically activate the Gαs‐protein‐mediated pathway, whereas EP4 receptors have strong biased activity for the Gαi‐protein‐mediated pathway. Thus, EP2 and EP4 receptors may not be similar Gαs‐coupled receptors but instead substantially different receptors with distinct roles.

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Cancer Chemoprevention Targeting COX‐2 using Dietary Phytochemicals

Chun¹,

Surh²

2014

Cancer and Inflammation Mechanisms

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EP2 and EP4 prostanoid receptor signaling

Cited by 401 publications

References 36 publications

The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

The Gαs‐protein‐mediated pathway may be steadily stimulated by prostanoid EP2 receptors, but not by EP4 receptors

Cancer Chemoprevention Targeting COX‐2 using Dietary Phytochemicals

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