Biological function and transcriptional regulation of mouse peptidylarginine deiminase type IV gene, Padi4

• Project/Area Number: 16580071
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied biochemistry
• Research Institution: Ibaraki University
• Principal Investigator: TAKAHARA Hidenari Ibaraki University, College of Agriculture, Professor, 農学部, 教授 (30122063)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: peptidylarginine deiminase / Padi4 / monoclonal antibody / peritoneal macrophage / arthritis rheumatoides / autoantibody / systemic lupus erythematosus / pristine / 蛋白質アルギニン脱イミノ酵素 / マウスPadi4遺伝子 / 全身性エリテマトーデス / snRNP / PADi4

Research Abstract

Peptidylarginine deiminase is a enzyme which convert arginine residues to citrulline residues. We reported that genomics of murine PAD are involved into five gene cluster located in 4E1 region, resembling those of human PAD gene cluster. Recent study disclosed the association of functional haplotypes of the gene PADI4 (orthologue to Padi4) with rheumatoid arthritis. Therefore, function of PAD4 and characterization of the elements regulating PADI4 gene expression using experimental animals is crucial to understanding their involvement in tissue physiology and pathological conditions. We made monoclonal antibodies against murine PAD4 and found the nuclear localization of this enzyme in the peritoneal macrophage by immunohistochemisty of the antibody. Furthermore, pristine introduced into peritoneal cavity of mouse induced the expression of PAD4 gene and deiminated U1-70K peptide of snRNP. These data suggested that the conversion of arginine residues of U1-70K into citrulline residues evokes systemic lupus erythematosus. In fact, the PAD4 could deiminate the peptide of U1-70K, whereas the deimination of p30gag from MLV was not observed. These findings indicated that U1-70K is a specific substrate for PAD4 in the nucleus. Taken together, our research supported by this grant revealed the possible mechanism of autoantibody disease via the deimination of nuclear protein.

Research Products

• [Journal Article] NF-Y and Sp1/Sp3 are involved in the transcriptional regulation of the peptidylarginine deiminase type III gene (PADI3) in human keratinocytes. (2006)
  • Author(s): Dong S, Kanno T, Yamaki A, Kojima T, Shirawa M, Kawada A, Mechin, MC Chavanas S, Serre G, Simon M, Takahara H
  • Journal Title: Biochem. J (掲載決定)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Proteomics implicated peptidylarginine deiminase 2 optic nerve citullination in glaucoma pathogenesis (2006)
  • Author(s): Bhattacharya S, Crabb JS, Bonilha VL, Gu X, Takahara H, Crabb JW
  • Journal Title: Invest Ophth Vis Sci 47(掲載決定)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] NF-Y and Sp1/Sp3 are involved in the transcriptional regulation of the peptidylarginine deiminase type III gene (PADI3) in human keratinocytes. (2006)
  • Author(s): Dong S, Kanno T, Ayako Yamaki A, Kojima T, Shirawa M, Kawada A, Marie-Claire Mechin, MC Chavanas S, Guy Serre G, Simon M, Takahara H
  • Journal Title: Biochem.J (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Proteomics implicated peptidylarginine deiminase 2 optic nerve citullination in glaucoma pathogenesis (2006)
  • Author(s): Bhattacharya S, Crabb JS, Bonilha VL, Gu X, Takahara H, Crabb JW
  • Journal Title: Invest Ophth Vis Sci. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory effect of mizorubine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macropages (2005)
  • Author(s): Zhong B, Tajima M, Takahara H, Nochi H, Tamoto K, Tamura N, Kobayashi S, Tamura Y, Ikdeda M, Akimoto T, Yoshino S, Hashimoto H
  • Journal Title: Mod Rheumatol 15 Pages: 264-268
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The peptidylarginine deiminases expressed in human epidermis differ in their substrate specificities and subcellular locations (2005)
  • Author(s): Mechin MC, Enji M, Nachat R, Chavanas S, Charveron, M, Ishida-Yamamoto A, Serre G, Takahara H, Simon M.
  • Journal Title: Cellular and Molecular Life Sciences 62 Pages: 1984-1995
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of the expression of peptidylarginine deiminase type II gene (PADI2) in human keratinocytes involves Sp1 and Sp3 transcription factors (2005)
  • Author(s): Dong S, Kojima T, Shiraiwa M, Mechin MC, Chavanas S, Serre G, Simon M, Kawada A, Takahara H.
  • Journal Title: J. Invest. Dermatol. 124(印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Peptidylarginine deiminase isoforms 1-3 are expressed in the epidermis and involved in the deimination of K1 and Filaggrin (2005)
  • Author(s): Nachat R, Mechin MC, Takahara H, Chavanas S, Charveron M, Serre G, Simon M.
  • Journal Title: J. Invest. Dermatol. 124 Pages: 384-393
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of the expression of peptidylarginine deiminase type II gene (PADI2) in human keratinocytes involves Sp1 and Sp3 transcription factors (2005)
  • Author(s): Dong S, Kojima T, Shiraiwa M, Mechin MC, Chavanas S, Serve G, Simon M, Kawada A, Takahara H.
  • Journal Title: J.Invest.Dermatol. 124 Pages: 1026-1033
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Peptidylarginine deiminase isoforms 1-3 are expressed in the epidermis and involved in the deimination of K1 and Filaggrin (2005)
  • Author(s): Nachat R, Mechin MC, Takahara H, Chavanas S, Charveron M, Serre G, Simon M.
  • Journal Title: J.Invest.Dermatol. 124 Pages: 384-393
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The peptidylarginine deiminases expressed in human epidermis differ in their substrate specificities and subcellular locations (2005)
  • Author(s): Mechin MC, Enji M, Nachat R, Chavanas S, Charveron M, Ishida-Yamamoto A, Serre G, Tkahara G, Simon M.
  • Journal Title: Cellular and Molecular Life Sciences 62・17 Pages: 1984-1995
• [Journal Article] Inhibitory effect of mizorubine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macropages (2005)
  • Author(s): Zhong B, Tajima M, Takahara H, Nochi H, Tamato K, Tamura N, Kobayashi S, Tamura Y, Ikdeda M, Akimoto T, Yoshino S, Hashimoto H
  • Journal Title: Mod Rheumatol 15 Pages: 264-268
• [Journal Article] Regulation of the expression of peptidylarginine deiminase type II gene (PADI2) in human keratinocytes involves Sp1 and Sp3 transcription factors (2005)
  • Author(s): Dong S, Kojima T, Shiraiwa M, Mechin MC, Chavanas S, Serre G, Simon M, Kawada A, Takahara H.
  • Journal Title: J.Invest.Dermatol. 124(印刷中)
• [Journal Article] Peptidylarginine deiminase isoforms 1- 3 are expressed in the epidermis and involved in the deimination of K1 and Filaggrin (2005)
  • Author(s): Nachat R, Mechin MC, Takahara H, Chavanas S, Charveron M, Serre G, Simon M.
  • Journal Title: J.Invest.Dermatol. 124 Pages: 384-393
• [Journal Article] Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6 (2004)
  • Author(s): Chavanas S, Mechin MC, Takahara H, Kawada A, Nachat R, Serre G, Simon M.
  • Journal Title: Gene 330 Pages: 19-27
  • Description: 「研究成果報告書概要(和文)」より