Characterization of the signaling pathway involved in the transcriptional regulation of semaphorin 3A in normal human epidermal keratinocytes

• Project/Area Number: 16K19739
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Juntendo University
• Principal Investigator: KAMATA YAYOI 順天堂大学, 医学(系)研究科(研究院), 助教 (00410035)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 発現制御 / セマフォリン3A / 表皮角化細胞 / 神経反発因子 / シグナル伝達 / アレルギー / アトピー性皮膚炎 / かゆみ

Outline of Final Research Achievements

In this study, we investigated the signaling pathway involved in the transcriptional regulation of semaphorin 3A (Sema3A) in normal human epidermal keratinocytes (NHEK). The 5’-flanking region of Sema3A gene was cloned and a critical region for Sema3A promoter activity was identified. In this region, transcription factor binding sites including activator protein (AP)-1 were found. Chromatin immunoprecipitation assay revealed AP-1 bound to the proximal promoter. Up-regulation of Sema3A mRNA by calcium was significantly decreased by AP-1 inhibitor (T-5224). Similarly, it was also decreased by protein kinase C (PKC) α inhibitor (Go6976), MEK1/2 inhibitor (PD98059), and JNK inhibitor (SP600125). These results suggest that Sema3A expression in NHEK is mediated by the PKC/MAPK/AP-1 signaling axis in the proximal promoter, and provide a new insight to identify novel antipruritic drug targets.

Research Products

• [Journal Article] Oral administration of milk-derived phospholipids inhibits penetration of cutaneous nerve fibres into epidermis in a mouse model of acute dry skin (2017)
  • Author(s): Sakaguchi A, Kamata Y, Takahashi N, Matsuda H, Kosaka R, Umehara Y, Ogawa H, Tominaga M, Takamori K
  • Journal Title: Clinical and Experimental Dermatology Volume: 42 Issue: 8 Pages: 890-894
  • DOI: 10.1111/ced.13207
  • Peer Reviewed
• [Journal Article] Antimicrobial peptides human LL-37 and β-defensin-3 modulate the expression of nerve elongation factors in human epidermal keratinocytes (2017)
  • Author(s): Umehara Yoshie、Kamata Yayoi、Tominaga Mitsutoshi、Niyonsaba Fran?ois、Ogawa Hideoki、Takamori Kenji
  • Journal Title: Journal of Dermatological Science Volume: 88 Issue: 3 Pages: 365-367
  • DOI: 10.1016/j.jdermsci.2017.07.010
  • Peer Reviewed
• [Journal Article] Mechanisms and Treatments of Dry SkinInduced itch (2017)
  • Author(s): A Kamo、M Tominaga、Y Kamata、K Takamori
  • Journal Title: Journal of Clinical and Cosmetic Dermatology Volume: 1 Issue: 3 Pages: 1-7
  • DOI: 10.16966/2576-2826.114
  • Peer Reviewed / Open Access
• [Journal Article] Relationships among plasma granzyme B level, pruritus and dermatitis in patients with atopic dermatitis. (2016)
  • Author(s): Kamata Y, Kimura U, Matsuda H, Tengara S, Kamo A, Umehara Y, Iizumi K, Kawasaki H, Suga Y, Ogawa H, Tominaga M, Takamori K.
  • Journal Title: J Dermatol Sci Volume: 84 Issue: 3 Pages: 266-271
  • DOI: 10.1016/j.jdermsci.2016.09.009
  • Peer Reviewed
• [Journal Article] Possible anti-pruritic mechanisms of cyclosporine A in atopic dermatitis. (2016)
  • Author(s): Ko KC, Tominaga M, Kamata Y, Umehara Y, Matsuda H, Takahashi N, Kina K, Ogawa M, Ogawa H, Takamori K.
  • Journal Title: Acta Derm Venereol Volume: 未定 Issue: 5 Pages: 624-629
  • DOI: 10.2340/00015555-2318
  • Peer Reviewed / Open Access
• [Journal Article] Differences in therapeutic effects of topically applied corticosteroid and tacrolimus on atopic dermatitis-like symptoms in NC/Nga mice. (2016)
  • Author(s): Atsushi Noguchi, Mitsutoshi Tominaga, Nobuaki Takahashi, Hironori Matsuda, Yayoi Kamata, Yoshie Umehara, Ko Kyi Chan, Yasushi Suga, Hideoki Ogawa, Kenji Takamori
  • Journal Title: J Dermatol Sci Volume: 86 Issue: 1 Pages: 54-62
  • DOI: 10.1016/j.jdermsci.2016.12.015
  • Peer Reviewed
• [Journal Article] 神経反発因子に着眼したアトピー性皮膚炎のかゆみ治療薬の開発 (2016)
  • Author(s): 鎌田弥生、冨永光俊、梅原芳恵、髙森建二
  • Journal Title: アレルギーの臨床 Volume: 36 Pages: 58-63
  • Peer Reviewed
• [Journal Article] 皮膚疾患と痒み (2016)
  • Author(s): 冨永光俊、加茂敦子、鎌田弥生、梅原芳恵、髙森建二
  • Journal Title: アレルギー・免疫 Volume: 23 Pages: 54-66
  • Peer Reviewed
• [Presentation] Sema3A expression is regulated by calcium/PKC/MAPK/AP-1 signaling axis in normal human epidermal keratinocytes. (2017)
  • Author(s): Kamata Y, Umehara Y, Sakaguchi A, Suga Y, Tominaga M, Takamori K.
  • Organizer: 9th World Congress of Itch
  • Int'l Joint Research
• [Presentation] Calcium increases semaphorin 3A expression by activating PKC/MAPK/AP-1 signaling axis in normal human epidermal keratinocytes. (2017)
  • Author(s): Kamata Y, Umehara Y, Sakaguchi A, Suga Y, Ogawa H, Tominaga M, Takamori K.
  • Organizer: The 42st Annual Meeting of The Japanese Society for Investigative Dermatology
• [Presentation] 乳由来リン脂質の経口投与は急性ドライスキンモデルマウスにおける表皮内神経線維の増生を抑制する. (2017)
  • Author(s): 坂口安澄, 鎌田弥生, 高橋伸明, 松田浩則, 幸坂涼平, 梅原芳恵, 須賀康, 冨永光俊, 髙森建二.
  • Organizer: 第47回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
• [Presentation] Correlation analysis among plasma granzyme B level, pruritus and severity score in patients with atopic dermatitis. (2016)
  • Author(s): Kamata Y, Kimura U, Matsuda H, Tengara S, Suga Y, Ogawa H, Tominaga M, Takamori K
  • Organizer: The 41st Annual Meeting of The Japanese Society for Investigative Dermatology
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-12-09
• [Presentation] Effects of antimicrobial peptide LL-37 on expression of natural moisturizing factor-generating proteases in epidermal keratinocytes. (2016)
  • Author(s): Umehara Y, Kamata Y, Tominaga M, Niyonsaba F, Sakaguchi A, Ogawa H, Takamori K
  • Organizer: The 41st Annual Meeting of The Japanese Society for Investigative Dermatology
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-12-09
• [Presentation] Involvement of opioid systems in itch-related behavior of imiquimod-induced psoriasis-like dermatitis model. (2016)
  • Author(s): Takahashi N, Tominaga M, Kamata Y, Umehara Y, Matsuda H, Suga Y, Ogawa H, Takamori K
  • Organizer: The 41st Annual Meeting of The Japanese Society for Investigative Dermatology
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-12-09
• [Presentation] Serum lipocalin-2 is a potential biomarker for pruritus in patients with psoriasis. (2016)
  • Author(s): Tominaga M, Takahashi N, Kimura U, Kamata Y, Umehara Y, Suga Y, Ogawa H, Takamori K
  • Organizer: The 41st Annual Meeting of The Japanese Society for Investigative Dermatology
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-12-09
• [Presentation] Efficacy of kappa-opioid receptor agonist and mu-opioid receptor antagonist to treat itch in imiquimod-induced psoriasis-like dermatitis model. (2016)
  • Author(s): Takahashi N, Tominaga M, Kamata Y, Umehara Y, Matsuda H, Ogawa H, Takamori K
  • Organizer: 46th Annual European Society for Dermatological Research Meeting 2016
  • Place of Presentation: Technical University of Munich (Germany)
  • Year and Date: 2016-09-07
  • Int'l Joint Research
• [Presentation] ドラッグリポジショニングに向けたセマフォリン3A発現調節剤のin vitroスクリーニング (2016)
  • Author(s): 鎌田弥生、冨永光俊、坂口安澄、梅原芳恵、髙森建二
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
• [Book] Itch in Atopic Dermatitis Management. Itch - Management in Clinical Practice. (2016)
  • Author(s): Kamata Y, Tominaga M, Takamori K
  • Publisher: Karger AG
• [Book] 抗ヒスタミン薬．膠原病・リウマチ・アレルギー研修ノート (2016)
  • Author(s): 鎌田弥生、髙森建二
  • Publisher: 診断と治療社
• [Remarks] 順天堂大学環境医学研究所髙森グループ 研究紹介
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/kankyo_igaku/k4_takamori.html
• [Patent(Industrial Property Rights)] セマフォリン3A発現亢進剤 (2016)
  • Inventor(s): 臼杵靖剛、五十嵐靖之、髙森建二、鎌田弥生、冨永光俊、他3名
  • Industrial Property Rights Holder: 学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-091429
  • Filing Date: 2016-04-28