Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium

Firestein, Gary S.; Echeverri, Fernando; Yeo, Michele; Zvaifler, Nathan J.; Green, Douglas R.

doi:10.1073/pnas.94.20.10895

Cited by 336 publications

(271 citation statements)

References 36 publications

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“…However, the relative lack of synoviocyte death despite expression of the p53 tumor suppres- sor gene (3) is poorly understood. One possibility is that the p53 gene is abnormal in RA, although only a limited percentage of the p53 cDNA pool contains mutations (11). Alternatively, activation of the downstream machinery for apoptosis might not function effectively in synoviocytes.…”

Section: Discussionmentioning

confidence: 99%

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Cha¹,

Rosengren²,

Boyle³

et al. 2006

Arthritis & Rheumatism

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Objective. Although p53 is overexpressed in rheumatoid arthritis (RA) synovial tissue (ST), few synoviocytes undergo apoptosis. This could be partly due to low expression of proapoptotic genes. Deficient p53 upregulated modulator of apoptosis (PUMA), which is a major effector of p53-mediated cell death, could contribute to this phenomenon. To evaluate a method to induce apoptosis, the expression and function of PUMA was investigated in ST and cultured fibroblast-like synoviocytes (FLS).Methods. PUMA expression in ST was measured by immunohistochemistry, Western blot analysis, and quantitative polymerase chain reaction analysis. Ad-p53 and plasmids encoding hemagglutinin-tagged, fulllength PUMA expression vector (HA-PUMA), PUMA lacking the Bcl-2 homology 3 domain, or pCEP4 were used to transfect FLS. Apoptosis was quantified by trypan blue exclusion, DNA fragmentation, and caspase 3 activation.Results. PUMA protein was detected in RA ST, although most of the immunoreactive protein was localized to sublining cells rather than the intimal lining synoviocytes. Western blot analysis showed no difference between RA ST and osteoarthritis (OA) ST. PUMA messenger RNA was detected in RA and OA ST, although the amounts were markedly lower than in the spleen and FLS. To determine if PUMA was inducible, FLS were transduced with Ad-p53. Even though p53 protein was produced and p21 expression was increased, PUMA expression was not enhanced. Consistent with this observation, Ad-p53 did not induce apoptosis in FLS. However, HA-PUMA transfection into FLS resulted in rapid apoptosis with the activation of caspase 3.Conclusion. PUMA can induce apoptosis by FLS and represents a potential target in RA.

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Section: Discussionmentioning

confidence: 99%

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Cha¹,

Rosengren²,

Boyle³

et al. 2006

Arthritis & Rheumatism

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“…Since FR were accused as causal factors in a large number of diseases, these were sometimes referred as ''Free Radical Diseases''. Some of the important diseases and health issues in this category are cancer [61][62][63][64][65][66][67], cardiovascular diseases [68][69][70][71][72][73], atherosclerosis [74][75][76][77][78][79][80][81], neurological disorders [82][83][84][85][86], renal disorders [87][88][89][90], liver disorders [91][92][93], hypertension [50,94,95], rheumatoid arthritis [96,97], adult respiratory distress syndrome, auto-immune deficiency diseases [98,99], inflammation, degenerative disorders associated with aging [100][101][102][103], diabetes mellitus [104][105]…”

Section: Reactive Oxygen Species and Reactive Nitrogen Species Transimentioning

confidence: 99%

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

Singh

Chandra

Mahdi

et al. 2010

Indian J Clin Biochem

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The antioxidants are essential molecules in human system but are not miracle molecules. They are neither performance enhancers nor can prevent or cure diseases when taken in excess. Their supplemental value is debateable. In fact, many high quality clinical trials on antioxidant supplement have shown no effect or adverse outcomes ranging from morbidity to all cause mortality. Several Chochrane Meta-analysis and Markov Model techniques, which are presently best available statistical models to derive conclusive answers for comparing large number of trials, support these claims. Nevertheless none of these statistical techniques are flawless. Hence, more efforts are needed to develop perfect statistical model to analyze the pooled data and further double blind, placebo controlled interventional clinical trials, which are gold standard, should be implicitly conducted to get explicit answers. Superoxide dismutase (SOD), glutathione peroxidase and catalase are termed as primary antioxidants as these scavenge superoxide anion and hydrogen peroxide. All these three enzymes are inducible enzymes, thereby inherently meaning that body increases or decreases their activity as per requirement. Hence there is no need to attempt to manipulate their activity nor have such efforts been clinically useful. SOD administration has been tried in some conditions especially in cancer and myocardial infarction but has largely failed, probably because SOD is a large molecule and can not cross cell membrane. The dietary antioxidants, including nutrient antioxidants are chain breaking antioxidants and in tandem with enzyme antioxidants temper the reactive oxygen species (ROS) and reactive nitrogen species (RNS) within physiological limits. Since body is able to regulate its own requirements of enzyme antioxidants, the diet must provide adequate quantity of non-enzymic antioxidants to meet the normal requirements and provide protection in exigent condition. So far, there is no evidence that human tissues ever experience the torrent of reactive species and that in chronic conditions with mildly enhanced generation of reactive species, the body can meet them squarely if antioxidants defense system in tissues is biochemically optimized. We are not yet certain about optimal levels of antioxidants in tissues. Two ways have been used to assess them: first by dietary intake and second by measuring plasma levels. Lately determination of plasma/serum level of antioxidants is considered better index for diagnostic and prognostic purposes. The recommended levels for vitamin A, E and C and beta carotene are 2.2-2.8 lmol/l; 27.5-30 lmol/l; 40-50 lmol/l and 0.4-0.5 lmol/l, respectively. The requirement and recommended blood levels of other dietary antioxidants are not established. The resolved issues are (1) essential to scavenge excess of radical species (2) participants in redox homeostasis (3) selective antioxidants activity against radical species (4) there is no universal antioxidant and 5) therapeutic value in case of deficiency. The overar...

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“…FLS derived from RA synovial tissue display an autonomous invasive phenotype (1). RA FLS express oncogenes as well as somatic mutations of the tumor-suppressor gene p53 (2). In contrast to osteoarthritis FLS, RA FLS are capable of autonomous invasion of human cartilage in an engrafted coculture system in SCID mice (3).…”

mentioning

confidence: 99%

“…Overexpression of p53 and functional p53 mutations have been detected in cells and tissue derived from RA patients (2). Difficulty clarifying the contribution of p53 mutations to synovial hyperplasia has resulted largely from discrepancies in the detection rate of p53 mutations within tissues and FLS derived from RA patients (9).…”

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confidence: 99%

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

Leech

Lacey

Xue

et al. 2003

Arthritis & Rheumatism

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Objective. To study the capacity of macrophage migration inhibitory factor (MIF) to regulate proliferation, apoptosis, and p53 in an animal model of rheumatoid arthritis (RA) and in fibroblast-like synoviocytes (FLS) from humans with RA.Methods. Antigen-induced arthritis (AIA) was induced in MIF -/-mice and littermate controls. FLS were obtained from patients with RA. Western blotting and immunohistochemistry were used to measure p53 in cells and tissues. Apoptosis was detected in cells by flow cytometry using TUNEL and annexin V/propidium iodide labeling. Apoptosis in tissue was detected using TUNEL. Proliferation was assessed in cultured cells and tissue by 3 H-thymidine incorporation and Ki-67 immunostaining, respectively.Results. MIF inhibited p53 expression in human RA FLS. Levels of p53 were correspondingly increased in MIF -/-mouse tissues and cells. Spontaneous and sodium nitroprusside-induced apoptosis were significantly increased in MIF -/-cells. In vitro exposure of FLS to MIF reduced apoptosis and significantly induced FLS proliferation. Synoviocyte proliferation in MIF -/-mice was correspondingly reduced. A decrease in the severity of AIA in MIF -/-mice was associated with an increase in p53 and apoptosis in synovium. Evidence of in situ proliferation was scant in this model, and no difference in in situ proliferation was detectable in MIF -/-mice compared with wild-type mice.Conclusion. These results indicate a role for MIF in the regulation of p53 expression and p53-mediated events in the inflamed synovium and support the hypothesis that MIF is of critical importance in the pathogenesis of RA.

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Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium

Cited by 336 publications

References 36 publications

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

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