Growth regulation of primary human keratinocytes by prostaglandin E receptor EP2 and EP3 subtypes

Konger, Raymond L.; Malaviya, Rama; Pentland, Alice P.

doi:10.1016/s0167-4889(97)00114-6

Cited by 90 publications

(99 citation statements)

References 53 publications

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“…The EP 4 antagonist caused an early S-phase arrest of 3T6 fibroblasts, whereas the EP 1 antagonist-treatment of these cells was associated with a significant increase in G 0 /G 1 population with respect to control cells. However, we cannot rule out the presence of EP 2 or EP 3 receptors in 3T6 fibroblasts and their contribution to the control of their growth, because it has been described in other cell types (18,24). The hypothesis that PGE 2 regulates the cell cycle at different levels by interacting with specific subtype receptors also was supported by the data on the effect of AH-6809 and AH-23848B on cyclin levels.…”

Section: Discussionmentioning

confidence: 77%

Role of EP₁ and EP₄ PGE₂subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Sánchez

2002

American Journal of Physiology-Cell Physiology

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Recent studies have suggested that prostaglandin E2 (PGE2) subtype receptors (EP) are involved in cellular proliferation and tumor development. We studied the role of EP1 and EP4 PGE2 subtype receptor antagonists AH-6809 and AH-23848B, respectively, in serum-induced 3T6 fibroblast proliferation. This was significantly reduced in a dose-dependent manner (IC50 ϳ100 and ϳ30 M, respectively) to an almost complete inhibition, without any cytotoxic effect. However, the effect of each antagonist on 3T6 cell cycle progression clearly differed. Whereas the EP1 antagonist increased the G0/G1 population, the EP4 antagonist brought about an accumulation of cells in early S phase. These effects were associated with a decrease in cyclin D and E levels in AH-6809-treated 3T6 cells and lower cyclin A levels in AH-23848B-treated fibroblasts with respect to control cells. The G0/G1 accumulation caused by AH-6809 seems to be intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) dependent, because a 6-h 1 M thapsigargin treatment allowed G 0/G1-arrested cells to enter S phase. Similarly, treatment with 20 M forskolin for 6 h allowed S-phase and G 2/M progression of AH-23848B-treated cells. This study shows that the inhibitory effect of the EP 1 and EP4 antagonists on serum-induced 3T6 fibroblast growth is due to their effect at various levels of the cell cycle machinery, suggesting that PGE 2 interaction with its different subtype receptors regulates progression through the cell cycle by modulating cAMP and [Ca 2ϩ ]i. arachidonic acid; cyclooxygenase; prostaglandin G/H synthase; phospholipase A 2

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Section: Discussionmentioning

confidence: 77%

Role of EP₁ and EP₄ PGE₂subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Sánchez

2002

American Journal of Physiology-Cell Physiology

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“…While the effects of PGE 2 on epidermal keratinocytes are reasonably well understood [1,[43][44][45], there has been much less investigation in the effects of PGE 2 on human melanocytes. Several years ago we set out to determine the biologic effects of PGE 2 on human melanocytes, and showed that nanomolar concentrations of PGE 2 stimulated melanocyte dendricity [7].…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

Scott

Fricke

Fender

et al. 2007

Experimental Cell Research

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Prostaglandins are lipid signaling intermediates released by keratinocytes in response to ultraviolet irradiation (UVR) in the skin. The main prostaglandin released following UVR is PGE 2 , a ligand for 4 related G-protein coupled receptors (EP 1 , EP 2 , EP 3 and EP 4 ). Our previous work established that PGE 2 stimulates melanocyte dendrite formation through activation of the EP 1 and EP 3 receptors. The purpose of the present report is to define the signaling intermediates involved in EP 1 and EP 3 -dependent dendrite formation in human melanocytes. We recently showed that activation of the atypical PKCζ isoform stimulates melanocyte dendricity in response to treatment with lysophosphatidylcholine. We therefore examined the potential contribution of PKCζ activation on EP 1 and EP 3 -dependent dendrite formation in melanocytes. Stimulation of the EP 1 and EP 3 receptors by selective agonists activated PKCζ, and inhibition of PKCζ activation abrogated EP 1 and EP 3 -receptor mediated melanocyte dendricity. Because of the importance of Rho-GTP binding proteins in the regulation of melanocyte dendricity, we also examined the effect of EP 1 and EP 3 receptor activation on Rac and Rho activity. Neither Rac nor Rho was activated upon treatment with EP 1,3 -receptor agonists. We show that melanocytes express only the EP 3A1 isoform, but not the EP 3B receptor isoform, previously associated with Rho activation, consistent with a lack of Rho stimulation by EP 3 agonists. Our data suggest that PKCζ activation plays a predominant role in regulation of PGE 2 -dependent melanocyte dendricity.

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“…Multiple subtypes of the PGE 2 receptor are expressed in cilary epithelial cells (48), osteoblastic cells (49), kerotinocytes (50), fibroblasts (23), and platelets (51). Furthermore, human Jurkat cells express both EP2 and EP4 receptors; however, the expression of EP2 receptor is ϳ100-fold lower than that of EP4 receptors (52).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin Receptor Subtypes, EP3C and EP4, Mediate the Prostaglandin E2-induced cAMP Production and Sensitization of Sensory Neurons

Southall¹,

Vasko

2001

Journal of Biological Chemistry

168

150

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Although a number of prostaglandin E 2 (PGE 2 ) receptor subtypes have been cloned, limited studies have been performed to elucidate subtypes that subserve specific actions of this eicosanoid, in part because of a paucity of selective receptor antagonists. Using reverse transcription-polymerase chain reaction (PCR) and antisense oligonucleotides, we examined which prostaglandin E 2 receptor (EP receptor) subtypes are expressed in sensory neurons and which mediate the PGE 2 -induced increase in cAMP production and augmentation of peptide release. Reverse transcription-PCR of cDNA isolated from rat sensory neurons grown in culture revealed PCR products for the EP1, EP2, EP3C, and EP4 receptor subtypes but not the EP3A or EP3B. Preexposing neuronal cultures for 48 h to antisense oligonucleotides of EP3C and EP4 mRNA diminished expression of the respective receptors by ϳ80%, abolished the PGE 2 -stimulated production of cAMP, and blocked the ability of PGE 2 to augment release of immunoreactive substance P and calcitonin gene-related peptide. Pretreating with individual antisense against the EP2, EP3C, or EP4 receptors or combinations of missense oligonucleotides had no effect on PGE 2 -induced activity. Treatment with antisense to EP3C and EP4 receptor subtypes did not alter the ability of forskolin to increase cAMP or enhance peptide release. These results demonstrate that sensory neurons are capable of expressing multiple EP receptor subtypes but that only the EP3C and EP4 receptors mediate PGE 2 -induced sensitization of sensory neurons. Prostaglandin E 2 receptors (EP receptors)1 have been classified into four general subtypes, EP1, EP2, EP3, and EP4, based on cloning and pharmacological manipulations (1, 2). These receptors are G-protein-coupled, and binding of agonists results in activation of various transduction cascades depending on the receptor subtype activated and the cells being studied. Activation of the EP1 receptor in kidney tubule cells increases the concentration of intracellular calcium, phosphoinositol turnover, and PKC activity (3, 4). EP2 and EP4 receptors are coupled through G s (1) to increase intracellular cAMP in a number of preparations (5-8). The EP3 receptor undergoes post-transcriptional RNA splicing to produce multiple EP3 isoforms, and activation of these splice variants can increase calcium mobilization or either stimulate or inhibit cAMP production (9 -11). Because subtypes of the EP receptor can be linked to different transduction cascades in different types of cells, it is critical to determine which receptors and receptorassociated signal transduction pathways are responsible for specific physiological actions of E-series prostaglandins.Although PGE 2 has a number of diverse physiological actions (12), its role in pain and inflammation is of primary importance. Indeed, both the analgesic and the anti-inflammatory actions of the nonsteroidal anti-inflammatory drugs are attributed to their ability to inhibit prostaglandin synthesis (13). In addition, PGE 2 is produced at sites of ...

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Growth regulation of primary human keratinocytes by prostaglandin E receptor EP2 and EP3 subtypes

Cited by 90 publications

References 53 publications

Role of EP₁ and EP₄ PGE₂subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Role of EP₁ and EP₄ PGE₂subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

Prostaglandin Receptor Subtypes, EP3C and EP4, Mediate the Prostaglandin E2-induced cAMP Production and Sensitization of Sensory Neurons

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Growth regulation of primary human keratinocytes by prostaglandin E receptor EP2 and EP3 subtypes

Cited by 90 publications

References 53 publications

Role of EP1 and EP4 PGE2subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Role of EP1 and EP4 PGE2subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

Prostaglandin Receptor Subtypes, EP3C and EP4, Mediate the Prostaglandin E2-induced cAMP Production and Sensitization of Sensory Neurons

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Role of EP₁ and EP₄ PGE₂subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation

Role of EP₁ and EP₄ PGE₂subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation