Dominant-negative p53 mutations in rheumatoid arthritis

Han, Zhen; Boyle, David L.; Shi, Yan; Green, Douglas R.; Firestein, Gary S.

doi:10.1002/1529-0131(199906)42:6<1088::aid-anr4>3.0.co;2-e

Cited by 83 publications

(75 citation statements)

References 16 publications

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“…IL-6 is a key proinflammatory cytokine that is abundant in RA synovium and synovial tissue (46,47) and its transcription is suppressed by wild-type p53 (27). We have shown that some p53 mutations from RA patients interfere with the ability of wild-type p53 to inhibit IL-6 gene expression (23). Real-time PCR analysis of microdissected synovium indicated that those regions that had abundant p53 mutations expressed significantly greater amounts of IL-6 mRNA compared with regions containing predominantly wild-type p53.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the p53 mutations in RA are characterized by transition base changes (7,21) and have also been previously identified in human neoplastic tissue (22). Furthermore, certain p53 mutations in RA are dominant negative and can suppress endogenous wild-type p53 function (23). Inactivation of p53 protein can recapitulate many of the phenotypic changes observed in RA, such as increased proliferation and invasion of synovial cells (24,25).…”

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confidence: 95%

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Regional analysis ofp53mutations in rheumatoid arthritis synovium

Yamanishi

Boyle

Rosengren

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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The p53 tumor suppressor protein plays a central role in cell cycle regulation, DNA repair, and apoptosis. Recent studies indicate that DNA damage and somatic mutations in the p53 gene can occur because of genotoxic stress in many tissues, including the skin, colon, and synovium. Although somatic mutations in the p53 gene have been demonstrated in rheumatoid arthritis (RA) synovial tissue and synoviocytes, no information is available on the location or extent of p53 mutations. Using microdissected RA synovial tissue sections, we observed abundant p53 transition mutations, which are characteristic DNA damage caused by oxidative stress. p53 mutations, as well as p53 mRNA expression, were located mainly in the synovial intimal lining rather than the sublining (P < 0.01). Clusters of p53 mutant subclones were observed in some microdissected regions, suggesting oligoclonal expansion. Because IL-6 gene expression is regulated by wildtype p53, IL-6 mRNA expression in microdissected tissues was quantified by using real-time PCR. The regions with high rates of p53 mutations contained significantly greater amounts of IL-6 mRNA compared with the low mutation samples (P < 0.02). The microdissection findings suggest that p53 mutations are induced in RA synovial tissues by inflammatory oxidative stress. This process, as in sun-exposed skin and inflamed colonic epithelium, provides some of the mutant clones with a selective growth advantage. A relatively low percentage of cells containing p53 mutations can potentially affect neighboring cells and enhance inflammation through the elaboration of proinflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

Regional analysis ofp53mutations in rheumatoid arthritis synovium

Yamanishi

Boyle

Rosengren

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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195

138

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“…Thus, p21-deficeint synovial fibroblasts behave similarly to the RA synovial fibroblasts that lack p53 or express the mutant forms of p53. Furthermore, ectopic expression of p21 or overexpression of wild-type p53 reduces IL-6 and MMP-1 expression in RA synovial fibroblasts (53)(54)(55)(56)58). Collectively, these data suggest that p21 may be one of the nodal points through which p53 inhibits cytokines and MMPs (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These data suggest that a subset of synovial fibroblasts may possess an inactive form of p53. Overexpression of plasmids encoding the p53 mutants found in RA synovium suppresses wild-type p53 function, as indicated by the induction of known p53-regulated genes, including IL-6 (53,54) and MMP-1 (55,56), which are normally inhibited by wild-type p53. Additionally, mice deficient in p53 display enhanced experimental arthritis, elevated levels of IL-6 in the synovium, and increased spontaneous MMP-13 expression compared with wildtype mice (57).…”

Section: Discussionmentioning

confidence: 99%

IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Perlman

Bradley

Liu

et al. 2003

The Journal of Immunology

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During the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 ± 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = −0.76; p < 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G0/G1 phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G0/G1 cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.

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“…However, p53 expression is also upregulated during inflammation and infections. Synovia from rheumatoid arthritis patients exhibit dominant negative mutations of p53 and expression of p53 is also upregulated in the joints of these patients [6]. This increased level of p53 in arthritic synovium joints can be seen in the early stages of disease development [7].…”

Section: Introductionmentioning

confidence: 99%

Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53^−/− mice

2010

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Mice lacking the tumor suppressor gene p53 spontaneously develop T-cell lymphomas at a high rate, suggesting that in these mice lymphomas arise due to defective apoptosis mechanisms in T cells mediated by p53. However, a role of p53 in regulation of T-cell responses or apoptosis has been poorly defined. TCR-mediated signaling in the absence of CD28 costimulation induces both apoptosis and proliferation of naïve T cells from WT mice. In this report we show that, in response to TCR stimulation, T cells from naïve p53-deficient mice exhibited higher proliferation and drastically reduced apoptosis than WT T cells. CD28 costimulation enhanced the proliferation of TCR-stimulated WT and p53 À/À T cells, suggesting that p53 uncouples CD28-mediated antiapoptotic and proliferative signals. To evaluate the physiological significance of these findings, we transplanted OVA expressing-EG.7 tumor cells into WT and p53 À/À mice. Unlike WT mice, p53 À/À mice exhibited a robust tumor-resistant phenotype and developed cytotoxic T-cell responses against OVA. Collectively, these data support the hypothesis that p53 is an essential factor in negative regulation of T-cell responses and have implication for immunomodulation during treatment of cancers and other inflammatory conditions. Key words: p53 . T-cell apoptosis and immune responses Supporting Information available online IntroductionTransformation related protein 53 (Trp53 or p53) is a member of the p53 transcription factor family that regulates DNA repair, genomic integrity, DNA replication, cell proliferation and apoptosis [1][2][3]. It contains an N-terminal transactivation domain, a C-terminal tetramerization domain and a central DNA binding domain. Under normal conditions p53 is expressed at low levels in a variety of cell types. Exposure of cells to ionizing radiation, DNA damage, or certain cellular or physiological stresses leads to stabilization and activation of p53 and its pathway [2]. Once activated, p53 binds to target DNA and initiates transcription of target genes that directly or indirectly inhibit the cell cycle or induce cell death [4,5]. Lack of p53 expression or function is related to development of a vast variety of tumor types and a role for p53 in apoptosis of cells has been the subject of numerous studies for many years.Traditionally, increased expression p53 has been reported in conditions that favor tumoroigenesis, e.g. ionizing radiations. However, p53 expression is also upregulated during . This increased level of p53 in arthritic synovium joints can be seen in the early stages of disease development [7]. Further, lymphocytes from rheumatoid arthritis patients express lower levels of p53 mRNA and protein, and have an impaired ability to induce p53 expression after exposure to gamma radiation, which correlated with increased survival of CD4 1 and CD8 1 T cells after exposure to gamma radiation [8]. Mice lacking p53 also display increased susceptibility to experimentally induced autoimmune diseases. p53 À/À mice are more susceptible than WT mice to low...

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Dominant-negative p53 mutations in rheumatoid arthritis

Cited by 83 publications

References 16 publications

Regional analysis ofp53mutations in rheumatoid arthritis synovium

Regional analysis ofp53mutations in rheumatoid arthritis synovium

IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53^−/− mice

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Dominant-negative p53 mutations in rheumatoid arthritis

Cited by 83 publications

References 16 publications

Regional analysis ofp53mutations in rheumatoid arthritis synovium

Regional analysis ofp53mutations in rheumatoid arthritis synovium

IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53−/− mice

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Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53^−/− mice