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Life and Death in the Synovium
Arthritis Research & Therapy volume 1, Article number: S32 (1999)
Studies of the p53 tumor suppressor gene in rheumatoid arthritis (RA) have demonstrated somatic mutations in rheumatoid synovium and synoviocytes but not in RA skin or OA synovium . Most of the mutations identified in RA samples are also present in various neoplastic diseases, suggesting that they are dominant negative. To determine if RA mutations are dominant negative, site directed mutagenesis was used to produced two RA mutants: Asparagine>Serine at codon 239 (N239S) and Arginine>Stop at codon 213 (R213*) . Co-transfection experiments were performed using a construct containing the p53-responsive bax promoter construct with a luciferase reporter gene (bax-luc). Low levels of bax promoter activity were detected in HS68 cells co-transfected with bax-luc and empty vector, N239S, or R213*, indicating that the RA mutant lacked transcriptional activity. Transfection with wt and bax-luc led to a 10-fold increase in luciferase expression. When the wt gene was co-transfected with either of the mutants, there was a dose dependent inhibition of bax promoter activity. These data indicate that at least 2 of the p53 mutants identified in RA joint samples are dominant negative and suppress endogenous wild type p53 function.
Greater than 80% of the p53 mutations identified in synovium and cultured synoviocytes were G/A and T/C transitions. Such mutations are characteristic of oxidative deamination by nitric oxide and suggest that the mutagenic environment in chronically inflamed synovium contributes to alterations in the p53 gene. Mutations accumulate over time and specific alterations in the p53 gene, ultimately contributing to synoviocytes autonomy and perpetuation of disease. Other genes might also be altered in arthritis, and mutations in the H-ras gene were also recently reported in RA and OA synovium. The occurrence of somatic mutations secondary to inflammation indicates that a window of opportunity exists in RA after the initiation of disease, but before establishment of aggressive pannus.
Firestein GS, Echeverri F, Yeo M, Zvaifler NJ, Green DR: Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci USA. 1997, 94: 10895-10900. 10.1073/pnas.94.20.10895.
Han Z, Boyle DL, Shi Y, Green DR, Firestein GS: Dominant negative p53 mutations in rheumatoid arthritis. Arthritis Rheum. 1999, 42: 1088-1092. 10.1002/1529-0131(199906)42:6<1088::AID-ANR4>3.0.CO;2-E.
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Firestein, G.S. Life and Death in the Synovium. Arthritis Res Ther 1, S32 (1999) doi:10.1186/ar46
- Rheumatoid Arthritis
- Nitric Oxide
- Somatic Mutation
- Oxidative Deamination
- Inflame Synovium