title: UVB Stimulates the Expression of Endothelin B Receptor in Human Melanocytes via a Sequential Activation of the p38/MSK1/CREB/MITF Pathway Which Can Be Interrupted by a French Maritime Pine Bark Extract through a Direct Inactivation of MSK1.
abstract: Melanogenesis is the physiological process by which melanin is synthesized to protect the skin from UV damage. While paracrine interactions between keratinocytes and melanocytes are crucial for regulating epidermal pigmentation, the endothelin (EDN)-endothelin B-receptor (EDNRB) interaction is one of the key linkages. In this study, we found that a single exposure of normal human melanocytes (NHMs) with UVB stimulates the expression of EDNRB and its upstream transcription factor microphthalmia-associated transcription factor (MITF) at the transcriptional and translational levels. That stimulation can be abrogated by post-irradiation treatment with a French maritime pine bark extract (PBE). UVB stimulated the phosphorylation of p38 and c-jun N-terminal kinase (JNK), but not ERK, followed by the increased phosphorylation of MSK1 and CREB. The post-irradiation treatment with PBE did not affect the increased phosphorylation of p38 and JNK, but distinctly abrogated the phosphorylation of MSK1 and CREB. Post-irradiation treatment with the MSK1 inhibitor H89 significantly down-regulated the increased gene expression of MITF and EDNRB in UVB-exposed NHMs. Our findings indicate for the first time that the increased expression of MITF that leads to the up-regulation of melanocyte-specific proteins in UVB-exposed NHMs is mediated via activation of the p38/MSK1/CREB pathway but not the ERK/RSK/CREB pathway. The mode of action by PBE demonstrates that interrupting MSK1 activation is a new target for antioxidants including PBE which can serve as anti-pigmenting agents in a reactive oxygen species-depletion-independent manner.
authors.affiliation: Research and Development Division, Toyo Shinyaku Co., Ltd., 7-28 Yayoigaoka, Tosu, Saga, 841-0005, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tagashira
authors.affiliation: Research and Development Division, Toyo Shinyaku Co., Ltd., 7-28 Yayoigaoka, Tosu, Saga, 841-0005, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Miyamoto
authors.affiliation: Research and Development Division, Toyo Shinyaku Co., Ltd., 7-28 Yayoigaoka, Tosu, Saga, 841-0005, Japan.
authors.forename: Sei-Ichi
authors.initials: S
authors.lastname: Kitamura
authors.affiliation: Research and Development Division, Toyo Shinyaku Co., Ltd., 7-28 Yayoigaoka, Tosu, Saga, 841-0005, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Tsubata
authors.affiliation: Research and Development Division, Toyo Shinyaku Co., Ltd., 7-28 Yayoigaoka, Tosu, Saga, 841-0005, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Research and Development Division, Toyo Shinyaku Co., Ltd., 7-28 Yayoigaoka, Tosu, Saga, 841-0005, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Takagaki
authors.affiliation: Research Institute for Biological Functions, Chubu University, 1200 Matsumoto, Kasugai, Aichi, 487-8501, Japan.
authors.forename: Genji
authors.initials: G
authors.lastname: Imokawa
mesh_terms: D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D016232:Endothelins / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects; D008543:Melanins / Q000235:genetics; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010858:Pigmentation / Q000187:drug effects / Q000235:genetics; D028223:Pinus / Q000737:chemistry*; D024301:Plant Bark / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology*; D044023:Receptor, Endothelin B / Q000235:genetics*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D012867:Skin / Q000187:drug effects; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C000588596:EDNRB protein, human; D016232:Endothelins; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D010936:Plant Extracts; D044023:Receptor, Endothelin B; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases