Effects of UVB on E Prostanoid Receptor Expression in Murine Skin

Tober, Kathleen L.; Thomas‐Ahner, Jennifer M.; Kusewitt, Donna F.; Oberyszyn, Tatiana M.

doi:10.1038/sj.jid.5700502

Cited by 29 publications

(48 citation statements)

References 37 publications

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“…All of the known receptors, including EP1 and EP2, are expressed in mouse skin and several have been directly linked to UVB-and phorbol ester-induced skin inflammation and carcinogenesis (Thompson et al, 2001;Sung et al, 2006;Brouxhon et al, 2007;Chun et al, 2007). Thus, UVB has previously been reported to stimulate expression of EP1, EP2 and EP4 in mouse skin, but to reduce expression of EP3 (Tober et al, 2007). Moreover, modulating EP receptor expression or activity using genetic and pharmacological approaches has demonstrated that EP1, EP2 and/ or EP4 are critical mediators of the actions of UV light in the skin (Tober et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Also of note was our observation that EP1 and EP2 relative mRNA levels increased at intermediate doses of UVB (10 and/or 15 mJ/cm 2 ), suggesting that undifferentiated cells were more responsive to UVB than differentiated cells in this parameter. Recent studies using techniques in immunohistochemistry have shown that these receptors are localized in suprabasal keratinocytes in mouse skin (Tober et al, 2007). …”

Section: Discussionmentioning

confidence: 99%

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UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

Black

Gray

Shakarjian

et al. 2008

Toxicology and Applied Pharmacology

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Prostaglandins belong to a class of cyclic lipid-derived mediators synthesized from arachidonic acid via COX-1, COX-2 and various prostaglandin synthases. Members of this family include prostaglandins such as PGE 2 , PGF 2α , PGD 2 and PGI 2 (prostacyclin) as well as thromboxane. In the present studies we analyzed the effects of UVB on prostaglandin production and prostaglandin synthase expression in primary cultures of undifferentiated and calcium-differentiated mouse keratinocytes. Both cell types were found to constitutively synthesize PGE 2 , PGD 2 and the PGD 2 metabolite PGJ 2 . Twenty-four hr after treatment with UVB (25 mJ/cm 2 ), production of PGE 2 and PGJ 2 increased, while PGD 2 production decreased. This was associated with increased expression of COX-2 mRNA and protein. UVB (2.5 -25 mJ/cm 2 ) also caused marked increases in mRNA expression for the prostanoid synthases PGDS, mPGES-1, mPGES-2, PGFS and PGIS, as well as expression of receptors for PGE 2 (EP1 and EP2), PGD 2 (DP and CRTH2) and prostacyclin (IP). UVB was more effective in inducing COX-2 and DP in differentiated cells and EP1 and IP in undifferentiated cells. UVB readily activated keratinocyte PI-3-kinase (PI3K)/Akt, JNK and p38 MAP signaling pathways which are known to regulate COX-2 expression. While inhibition of PI3K suppressed UVB-induced mPGES-1 and CRTH2 expression, JNK inhibition suppressed mPGES-1, PGIS, EP2 and CRTH2, and p38 kinase inhibition only suppressed EP1 and EP2. These data indicate that UVB modulates expression of prostaglandin synthases and receptors by distinct mechanisms. Moreover, both the capacity of keratinocytes to generate prostaglandins and their ability to respond to these lipid mediators are stimulated by exposure to UVB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

Black

Gray

Shakarjian

et al. 2008

Toxicology and Applied Pharmacology

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“…The effects of prostaglandins and the cross talk between prostaglandin receptors and their signaling intermediates are of intense interest because of the diverse effects of prostaglandins on cell growth, differentiation and carcinogenesis [3,38,[41][42][43]. 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.…”

Section: Discussionmentioning

confidence: 99%

“…In murine and human skin EP 3 receptor expression is localized to the basal layer of the epidermis within keratinocytes [37,38]. To co-localize EP 3 receptor expression in melanocytes, contiguous skin sections were stained with the melanocyte specific antibody Melan-a and with antibodies to EP 3 .…”

Section: Melanocytes Express the Ep 3 Receptor In Skin In Vivomentioning

confidence: 99%

“…EP 3 was strongly expressed in basal keratinocytes, and EP 3 co-localized with melanocytes ( Figure 4). In murine and human skin EP 1 receptor expression is localized to the upper differentiated layers of the epidermis [38][39][40], with little or no localization to the basal epidermal layers where melanocytes reside. Immunocytochemical staining of skin sections for EP 1 receptor showed weak positive staining in the upper spinous layer of the epidermis, without expression in melanocytes (data not shown).…”

Section: Melanocytes Express the Ep 3 Receptor In Skin In Vivomentioning

confidence: 99%

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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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Chromosomal aberrations in UVB‐induced tumors of immunosuppressed mice

Dworkin

Tober

Duncan

et al. 2009

Genes Chromosomes & Cancer

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In immunocompromised individuals, such as organ transplant recipients, the risk of cutaneous squamous cell carcinoma (SCC) is increased 60-250 fold, and there is an increased likelihood to develop aggressive, metastatic SCC. An understanding of the genes involved in SCC tumorigenesis is critical to prevent SCC-associated morbidity and mortality. Mouse models show that different immunosuppressive drugs lead to SCCs varying in size, number, and malignant potential. In this study we utilized mouse models that mimic adult transplant recipients to study the effect of immunosuppressive drugs and UV light on SCC development. UV-induced tumors from six treatment groups, control, tacrolimus (Tac), rapamycin (Rap), cyclosporin (CsA), mycophenolate mofetil (MMF), and Rap plus CsA, were evaluated by array comparative genomic hybridication. Mouse SCCs appear to show similar genomic aberrations as those reported in human SCCs and offer the ability to identify genomic changes associated with specific and combinatorial effects of drugs. Fewer aberrations were seen in tumors of mice treated with MMF or Rap. Tumors from Tac treated animals showed the highest number of changes. Calcineurin inhibitors (Tac and CsA) did not cluster together by their genomic aberrations, indicating their contribution to UV mediated carcinogenesis may be through different pathways. The combination treatment (Rap plus CsA) did not cluster with either treatment individually, suggesting it may influence SCC tumorigenesis via a different mechanism. Future studies will identify specific genes mapping to regions of aberration that are different between treatment groups to identify target pathways that may be affected by these drugs.

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Effects of UVB on E Prostanoid Receptor Expression in Murine Skin

Cited by 29 publications

References 37 publications

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

Chromosomal aberrations in UVB‐induced tumors of immunosuppressed mice

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