Research of rheumatoid arthritis using Dbl knock-out mice

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Rheumatoid arthritis (RA) is a chronic polyarthritis finally leading to joint destruction. While the ratio of the risk for siblings of patients with a disease was much greater in familial RA, suggesting that genetic factors may be important as a cause of familial clustering, we have previously reported in Japanese familial RA with 3 principal chromosomal regions of linkage, D1S253/214, D8S556 and DXS1232. Komai et al. have subsequently identified DBL proto-oncogene (wild type DBL; GenBank/EMBL/DDBJ Accession No.AB085902) located on DXS1232/984 as a candidate for RA disease gene : a mutant DBL cDNA lacking exons 23 and 24 (deleted type DBL ; GenBank/EMBL/DDBJ Accession No. AB085901) was associated with familial RA.The DBL proto-oncogene is a prototype guanine nucleotide exchange factor (GEF) that modulates activity of small G proteins, including Rho family GTPases, RhoA and Cdc42 and possibly Rac1. Dbl converts the client proteins from the GDP-bound (inactive) form to the GTP-bound (act … More ive) form, allowing its effector domain to interact with downstream signaling molecules. Previous studies have shown that the Rho family GTPases control actin cytoskeleton organization and modulate movement, proliferation, and apoptosis of the cell. In humans, Rho family GEFs play important roles in the maturation and organization of skeletal muscles or nerves, also in the maturation and cytokine production of lymphoid cells. The mutation in some of the GEF family genes has been implicated in the human disease such as faciogenital dysplasia ^<15)>. It have been reported that deleted form of Dbl showed a weaker GEF activity toward Cdc42, and that infiltration and NADPH oxidase activity of neutrophils were significantly decreased in rheumatoid patients with this deleted mutant DBL.In the present study, we established mouse embryonic fibroblast(MEF) cell lines from Dbl knock-out mice and evaluated the activity of Rho family proteins and the intracellular localization and mobility of Dbl protein in mutant or wild type MEFs. The result showed that Dbl proto-oncogene affect the activation of Rho family proteins in MEFs through the decrease of intracellular mobility. We are now going to back-cross Dbl knock-out mice with DBIJ mice to examine the effects of Dbl gene-deletion on collagen-induced arthritis in mice. Less