ロリクリンの変異が角化細胞のアポトーシスに及ぼす影響

• Project/Area Number: 11877138
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Dermatology
• Research Institution: Asahikawa Medical College
• Principal Investigator: 山本 明美 旭川医科大学, 医学部, 講師 (30241441)
• Co-Investigator(Kenkyū-buntansha): 高橋 英俊 旭川医科大学, 医学部, 講師 (00216748)
• Project Period (FY): 1999 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥2,100,000 (Direct Cost: ¥2,100,000); Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 1999: ¥700,000 (Direct Cost: ¥700,000)
• Keywords: 表皮 / 辺縁帯 / ロリクリン / 核移行シグナル / インボルクリン / シスタチンA / 角化症 / 紫外線 / ロリクリン角皮症 / アポトーシス / Vohwinkel症候群 / TUNEL法

Research Abstract

ロリクリン角皮症の概念の確立
辺縁帯の主成分ロリクリンの遺伝子異常による角化異常症は我々が発見した疾患であるが、本研究の期間中にも新しい家系を発見し、これらを「ロリクリン角皮症」という概念で包括した(J Dermatol Sci, 1999, Br J Dermatol 2001)。
ロリクリン角皮症における細胞死過程の解析
ロリクリン角皮症患者では顆粒層、角層の細胞の核は断片化DNAとプロフィラグリンアミノ末端ドメインを有していたため本症では細胞死の頓挫の状態にあることが示唆された。また、ロリクリン角皮症患者の発現する変異蛋白に対する抗体を作成し、その局在を検討したこところ、変異蛋白は辺縁帯には移行せず、これらの断片化DNAを含む核に蓄積されていることを明らかにした(J Invest Dermatol, 2000)。
インボルクリンとシスタチンAの遺伝子発現調節機構
辺縁帯の成分であるインボルクリンとシスタチンAの遺伝子発現調節機構を明らかにした(Biochem J, 1999, BBRC, 2000)。
辺縁帯形成におけるエピトープマスキング
辺縁帯形成過程にいてデスモゾーム部分でロリクリンの抗原エピトープのマスクキングがおきることを照明した(Exp Dermatol, 1999)。
角化細胞のアポトーシスの機序
紫外線による角化細胞のアポトーシスはFasリガンドの結合なしにFas抗原の多量体形成によることで起きること(J Invest Dermatol Symp Proc 2001), Bcl-2はこれを抑制することを示した(Photochem Photobiol 2001)。

Research Products

• [Publications] Ishida-Yamamoto A: "Antigen retrieval of loricrin epitopes at desmosomal areas of cornified cell envelopes : an immunoelectron microscopic analysis"Exp Dermatol. 8. 402-406 (1999)
• [Publications] Takahashi H: "Interferon-γ-dependent stimulation of human involucrin gene expression : STAT-1 protein activates involucrin promoter activity"Biochem J. 344. 797-802 (1999)
• [Publications] Takahashi H: "Loricrin gene mutation in a Japanese patient of Vohwinkel's syndrome"J Dermatol Sci. 19. 44-47 (1999)
• [Publications] Ishida-Yamamoto, A: "Mutant loricrin is not crosslinked into the cornified cell envelopes but is translocated into the nuclei in loricrin keratoderma"J Invest Dermatol. 115. 1095-1103 (2000)
• [Publications] Takahashi H: "Transcriptional factor AP-2γ increases human cystatin A gene transcription of keratinocytes"BBRC. 278. 719-723 (2000)
• [Publications] Matsumoto K: "Loricrin keratoderma : a cause of congenital ichthyosiform erythroderma and collodion baby"Br J Dermatol. 145. 657-660 (2001)
• [Publications] Ishida-Yamamoto A: "Antigen retrieval of loricrin epitopes at desmosomal areas of cornified cell envelopes : an immunoelectron microscopic analysis."Exp Dermatol. 8. 402-406 (1999)
• [Publications] Ishida-Yamamoto A: "Electron microscopic in situ DNA nick end-labeling and combination with immunoelectron microscopy"J Histochem Cytochem. 47. 711-717 (1999)
• [Publications] Tamai K: "Recurrent COL7A1 mutations in Japanese patients with dystrophic epidermolysis bullosa : positional effects of premature termination codon mutations on clinical severity"J Invest Dermatol. 112. 991-993 (1999)
• [Publications] Ishida-Yamamoto A: "Programmed cell death in normal epidermis and loricrin keratoderma. Multiple functions of profilaggrin in keratinization"J Invest Dermatol Symposium Proceedings. 4. 145-149 (1999)
• [Publications] Takahashi H: "Interferon-γ-dependent stimulation of human involucrin gene expression : STAT-1 protein activates involucrin promoter activity"Biochem J. 344. 797-802 (1999)
• [Publications] Takahashi H: "Loricrin gene mutation in a Japanese patient of Vohwinkel's syndrome"J Dermatol Sci. 19. 44-47 (1999)
• [Publications] Takahashi H: "Fas antigen modulates ultraviolet B (UVB) -induced apoptosis of SVHK cells : sequential activation of caspases 8,3, and 1 in the apoptotic process"Exp Cell Res. 249. 291-298 (1999)
• [Publications] Ishida-Yamamoto A: "Mutant loricrin is not crosslinked into the cornified cell envelopes but is translocated into the nuclei in loricrin keratoderma"J Invest Dermatol. 115. 1095-1103 (2000)
• [Publications] Ishida-Yamamoto A: "A case of erythrokeratodormia variabilis without mutations in connexin31"Br J Dermatol. 143. 1283-1287 (2000)
• [Publications] Ishida-Yamamoto A: "Decreased deiminated keratin K1 in psoriatic hyperproliferative epidermis"J Invest Dermatol. 114. 701-705 (2000)
• [Publications] Ishida-Yamamoto A: "Immunoelectron microscopy links molecules and morphology in the studies of keratinization"Eur J Dermatol. 10. 429-435 (2000)
• [Publications] Takahashi H: "Copper, zinc-superoxide dismutase protects from ultraviolet B-induced apoptosis in SV40-transformed human keratinocytes : the protection is associated with the increased levels of antioxidant enzyme"J Dermatol Sci. 23. 12-21 (2000)
• [Publications] Takahashi H: "Transcriptional factor AP-2γ increases human cystatin A gene transcription of keratinocytes"Biochem Biophys Res Commun. 278. 719-723 (2000)
• [Publications] Takahashi H: "Cornified cell envelope formation is distinct from apoptosis in epidermal keratinocytes"J Dermatol Sci. 23. 161-169 (2000)
• [Publications] Takahashi, H. et al.: "Loricrin gene mutation in a Japananese patient of Vohwinkel's syndrome"J.Dermatol Sci. 19. 44-47 (1999)
• [Publications] Ishida-Yamamoto, A. et al.: "Electron microscopic in situ DNA nick end-labeling and combination with immunoelectron microscopy"J.Histochem Cytochem. 47. 711-717 (1999)
• [Publications] Ishida-Yamamoto, A. et al.: "Mutant loricrin is not crosslinked into the cornified cell envelopes but translocated into the nuclei in loricrin keratoderma"J.Invest Dermatol. 112. 551 (1999)
• [Publications] Ishida-Yamamoto, A. et al.: "Antigen retrieval of loricrin epitopes at desmosomal areas of cornified cell envelopes : an immunoelectron microscopic analysis"Exp Dermatol. 8. 402-406 (1999)