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CUL1, a component of E3 ubiquitin ligase, alters lymphocyte signal transduction with possible effect on rheumatoid arthritis

Genes & Immunity volume 6, pages 194–202 (2005)Cite this article

Abstract

Ubiquitination affects various immune processes and E3 ubiquitin ligases (E3) play an important role in determining substrate specificity. We identified 11 human E3 ligase genes of potential importance in pathogenesis of autoimmune diseases by search of public databases and screened them for candidacy of biological investigation with case–control linkage disequilibrium tests on multiple SNPs in the genes using rheumatoid arthritis (RA) as a model of autoimmune diseases. Significant association with RA was observed in an SNP in intron 3 of Cullin 1 (CUL1) that affected transcriptional efficiency of the promoter activity in lymphocytic cell lines. Quantitative expression analysis revealed that CUL1 mRNA was highly detected in lymphoid tissues including spleen and tonsil, and was specifically expressed in T and B lymphocytes in fractionated peripheral leukocytes. Histological evaluation of tonsils indicated that CUL1 protein expression was relatively specific for maturing germinal centers. Suppression of CUL1 expression had influence on the phenotype of T-cell line, that is, it inhibited IL-8 induction, which is known to play an important role in the migration of inflammatory cells into the affected area seen in RA. Our data suggest that the regulation of CUL1 expression in immunological tissues may affect the susceptibility of RA via altering lymphocyte signal transduction.

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Acknowledgements

We thank members of the Laboratory for Rheumatic Diseases for their technical assistance; H Kawakami and T Kawaguchi for their computer programming; S Yoshino for clinical samples; K Watanabe and T Hirai for assistance in search of various kinds of databases; M Ono, T Takahashi, T Ohtsuka and M Nakayama for discussions. This work was supported by a grant from the Japanese Millenium Project.

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Authors and Affiliations

  1. SNP Research Center, RIKEN, Yokohama, Kanagawa, Japan

    R Kawaida, R Yamada, K Kobayashi, S Tokuhiro, A Suzuki, Y Kochi, X Chang, A Sekine, T Tsunoda, Y Nakamura & K Yamamoto

  2. Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Y Kochi, T Sawada & K Yamamoto

  3. Biomedical Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan

    R Kawaida, S Tokuhiro & H Furukawa

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  1. R Kawaida
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Correspondence to R Yamada.

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Kawaida, R., Yamada, R., Kobayashi, K. et al. CUL1, a component of E3 ubiquitin ligase, alters lymphocyte signal transduction with possible effect on rheumatoid arthritis. Genes Immun 6, 194–202 (2005). https://doi.org/10.1038/sj.gene.6364177

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