Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The healthy synovial lining layer consists of a single cell layer that regulates the transport between the joint cavity and the surrounding tissue. It has been suggested that abnormalities such as somatic mutations in the p53 tumor-suppressor gene contribute to synovial hyperplasia and invasion in rheumatoid arthritis (RA). In this study, expression of epithelial markers on healthy and diseased synovial lining tissue was examined. In addition, we investigated whether a regulated process, resembling epithelial to mesenchymal transition (EMT)/fibrosis, could be responsible for the altered phenotype of the synovial lining layer in RA. Synovial tissue from healthy subjects and RA patients was obtained during arthroscopy. To detect signs of EMT, expression of E-cadherin (epithelial marker), collagen type IV (indicator of the presence of a basement membrane) and alpha-smooth muscle actin (alpha-sma; a myofibroblast marker) was investigated on frozen tissue sections using immunohistochemistry. Fibroblast-like synoviocytes (FLSs) from healthy subjects were isolated and subjected to stimulation with synovial fluid (SF) from two RA patients and to transforming growth factor (TGF)-beta. To detect whether EMT/fibrotic markers were increased, expression of collagen type I, alpha-sma and telopeptide lysylhydroxylase (TLH) was measured by real time PCR. Expression of E-cadherin and collagen type IV was found in healthy and arthritic synovial tissue. Expression of alpha-sma was only found in the synovial lining layer of RA patients. Stimulation of healthy FLSs with SF resulted in an upregulation of alpha-sma and TLH mRNA. Collagen type I and TLH mRNA were upregulated after stimulation with TGF-beta. Addition of bone morphogenetic protein (BMP)-7 to healthy FLS stimulated with SF inhibited the expression of alpha-sma mRNA. The finding that E-cadherin and collagen type IV are expressed in the lining layer of healthy and arthritic synovium indicates that these lining cells display an epithelial-like phenotype. In addition, the presence of alpha-sma in the synovial lining layer of RA patients and induction of fibrotic markers in healthy FLSs by SF from RA patients indicate that a regulated process comparable to EMT might cause the alteration in phenotype of RA FLSs. Therefore, BMP-7 may represent a promising agent to counteract the transition imposed on synoviocytes in the RA joint.
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PMID:Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics. 1707 92

Anti-TNF-alpha [anti-(tumour necrosis factor-alpha)] therapy is widely considered to be among the most efficient treatments available for rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. In the present study a tetravalent mini-antibody, named 'TNF-TeAb', was constructed by fusing the tetramerization domain of human p53 to the C-terminus of an anti-TNF-scFv [anti-(TNF-alpha-single-chain variable fragment)] via a long and flexible linking peptide derived from human serum albumin. TNF-TeAb was overexpressed as inclusion bodies in the cytoplasm of Escherichia coli, purified to homogeneity by immobilized- metal affinity chromtaography under denaturing conditions and produced in functional form by using an in vitro refolding system. In vitro bioactivity assays suggested that tetramerization of TNF-scFv resulted in an enormous gain in avidity, which endowed TNF-TeAb with a stronger ability to inhibit both receptor binding and cytolytic activity of TNF-alpha. TNF-alpha targeting therapy in rats with collagen-induced arthritis demonstrated that TNF-TeAb provided a much more significant therapeutic effect than did TNF-scFv in suppressing arthritis progression, attenuating inflammation and destruction in joints, and down-regulating pro-inflammatory cytokines and anti-(type II collagen) antibody. The conclusions are therefore (i) that multimerization of the antibody fragment by a self-association peptide is an efficient way to increase its avidity and (ii) that TNF-TeAb has potential applicability for anti-TNF-alpha therapy.
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PMID:Targeting TNF-alpha with a tetravalent mini-antibody TNF-TeAb. 1747 72

Curcumin is the active ingredient of turmeric that has been consumed as a dietary spice for ages. Turmeric is widely used in traditional Indian medicine to cure biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. Extensive investigation over the last five decades has indicated that curcumin reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms associated with type II diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, inhibits HIV replication, enhances wound healing, protects from liver injury, increases bile secretion, protects from cataract formation, and protects from pulmonary toxicity and fibrosis. Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects. These include the regulation of signal transduction pathways and direct modulation of several enzymatic activities. Most of these signaling cascades lead to the activation of transcription factors. Curcumin has been found to modulate the activity of several key transcription factors and, in turn, the cellular expression profiles. Curcumin has been shown to elicit vital cellular responses such as cell cycle arrest, apoptosis, and differentiation by activating a cascade of molecular events. In this chapter, we briefly review the effects of curcumin on transcription factors NF-KB, AP-1, Egr-1, STATs, PPAR-gamma, beta-catenin, nrf2, EpRE, p53, CBP, and androgen receptor (AR) and AR-related cofactors giving major emphasis to the molecular mechanisms of its action.
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PMID:Modulation of transcription factors by curcumin. 1756 8

Endopalsmic reticulum (ER) is specialized organelle to maintain the integrity of secreted and membranous proteins. ER also senses so-called "ER stress", which is a result of various internal and external stresses, and triggers apoptosis when the diverse attempts to accommodate with the stress are in fail. The impairment these ER functions has been implicated in several human diseases, in which aberrant ER stress induced apoptosis is observed. We discuss about another disease model related with ER mediated apoptosis based on the recent studies about Synoviolin, an E3 ubiquitin ligase inherently utilized for ER associated degradation (ERAD). In addition to its canonical role in ERAD, Synoviolin targets tumor suppressor gene p53 for proteasomal degradation, suggesting the crosstalk between ERAD and p53 mediated apoptotic pathway under ER stress. Together with the anti-apoptotic property of Synoviolin previously elucidated by both in vitro and in vivo analyses, its new function in p53 regulation may provide a new insight into the pathomechanism of proliferative diseases such as cancer or rheumatoid arthritis.
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PMID:The roles of synoviolin in crosstalk between endoplasmic reticulum stress-induced apoptosis and p53 pathway. 1758 19

Over expression of P53 has been described in many inflammatory conditions including rheumatoid arthritis (RA) and osteoarthritis (OA) as a protective mechanism to induce apoptosis of synovial cells. Lack of P53 function through mutation in human synoviocytes increases the development of normal synovial fibroblasts into transformed aggressive synovial fibroblasts. P53 levels were determined in supernatant of cultured mononuclear cells (MCs) isolated from peripheral blood (PBMCs) of patients with RA (n = 10) and OA (n = 10) as well as 10 normal healthy controls (C). P53 levels were also determined in supernatants of MCs isolated from synovial fluid (SFMCs) of RA and OA patients. Results of this work revealed that P53 level was significantly higher in PBMCs supernatant of RA group than those of both (C) and (OA) groups (P = 0.022). P53 level was non-significantly higher in SFMCs supernatant of RA than OA group. Significantly higher levels of P53 was detected in SFMCs culture supernatant than that of PBMCs within each RA (P = 0.003) and OA (P = 0.001) group. Results also showed a significantly positive correlation between P53 levels (in both PBMCs and SFMCs) and the disease activity score (DAS) in RA group (P = 0.01, P = 0.02 respectively) while insignificantly positive correlations between P53 level (in both PBMCs and SFMCs) and radiological grading of OA group were obtained. These results indicate that mutations and consequent dysfunction of P53 gene may result in chronic inflammation and hyperplasia in RA patients. In conclusion, gene therapy targeting P53-dependent pathway could be a promising therapy for RA and OA diseases.
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PMID:Study of P53 in peripheral blood and synovial mononuclear cells of rheumatoid arthritis and osteoarthritis patients and its relation to the degree of disease activity. 1797 11

Leflunomide has recently been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis. This approval was based on data from double-blind multicentre trials in the US (US 301; leflunomide versus methotrexate versus placebo) and multicentre European trials (leflunomide versus sulfasalazine versus placebo, and leflunomide versus methotrexate versus placebo). In these trials, leflunomide was superior to placebo and similar to methotrexate or sulfasalazine in efficacy and adverse effects. Both methotrexate and leflunomide retarded the rate of radiological progression, entitling them to qualify as disease-modifying agents (DMARDs). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHO-DH by A77-1726, the active metabolite of leflunomide, occurs at concentrations (approximately 600 nmol/L) that are achieved during treatment of rheumatoid arthritis. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with cell cycle progression. This is mediated by inadequate production of rUMP and utilises mechanisms involving the sensor protein p53. The relative lack of toxicity of A77-1726 on nonlymphoid cells may be due to the ability of these cells to fulfil their ribonucleotide requirements by use of the salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.
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PMID:How does leflunomide modulate the immune response in rheumatoid arthritis? 1803 Nov 84

The metastasis-associated protein S100A4 belongs to the large family of S100 calcium-binding proteins that appear to play regulatory roles in diverse biological activities. Moreover, a prognostic role of S100A4 has been suggested for patients with several types of cancer. Cancer promoting properties for S100A4 have been demonstrated, particularly through its regulation of cell motility, proliferation and apoptosis, as well as by stimulation of angiogenesis and remodelling of the extracellular matrix. Increased expression of S100A4 mRNA has been detected in proliferating synovial fibroblasts in rheumatoid arthritis. Furthermore, strong upregulation of the S100A4 protein in rheumatoid arthritis synovial tissue compared with osteoarthritis and control tissues has been demonstrated recently, especially at sites of joint invasion. Several immune and vascular cells were also identified to be producing S100A4 within the synovium. The local upregulation of S100A4 was accompanied by high plasma and synovial fluid concentrations of the S100A4 protein existing in the bioactive oligomeric form in patients with rheumatoid arthritis. Consistent with data from cancer studies, the extracellular S100A4 oligomer appears to be involved in regulation of several matrix-degrading enzymes and modulation of the transcriptional activation function of the tumour suppressor protein p53 in rheumatoid arthritis synovial fibroblasts. Taken together, one can speculate that increased S100A4 protein in circulation and locally at sites of inflammation, particularly at sites of joint destruction, might be linked to the process of aggressive fibroblast behaviour contributing to the pathogenesis of chronic autoinflammatory diseases such as rheumatoid arthritis.
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PMID:The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts. 1805 57

p53 is a transcription factor with a well-described role in the induction of apoptosis and cell cycle arrest as part of a protective response to a variety of stressful stimuli. Expansion of inflamed tissue in rheumatoid arthritis has been related to the loss of functioning p53, and the severity of collagen-induced arthritis is increased in p53-/- mice. Our objective was to assess the role of p53 in a model of adaptive immunity, antigen-induced arthritis (AIA). AIA was induced in p53-/- and wild-type mice by priming with methylated bovine serum albumin followed by intra-articular challenge. Severity of arthritis was assessed using a standardized scoring system and synovial apoptosis was detected by TdT-mediated biotin-dUTP nick-end labelling. Splenocyte proliferation was measured by [H(3)] incorporation and interferon (IFN)-gamma release. Splenocyte viability was assessed using Titreglow. Splenic T cell activation status was assessed by flow cytometry. Serum cytokines were measured using enzyme-linked immunosorbent assay. Increased severity of AIA in p53-/- mice was associated with decreased synovial apoptosis and with increased delayed-type hypersensitivity response, increased mitogen and antigen-induced splenocyte proliferation and increased IFN-gamma release in p53-/- mice compared with wild-type mice. Antigen-specific immunoglobulin responses were equivalent in both groups. Splenocyte viability was increased in p53-/- mice but T cell apoptosis was equivalent. T cell activation markers were increased in p53-/- mice compared with wild-type mice. Lipopolysaccharide-induced tumour necrosis factor release was increased in p53-/- mice with a trend to increased interleukin-6 in p53-/- mice compared with littermates. p53 is involved in the modulation of adaptive and innate immune responses relevant to arthritis models and is also involved in the modulation of severity of AIA by both cell-cycle dependent and cell-cycle-independent mechanisms.
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PMID:The tumour suppressor gene p53 modulates the severity of antigen-induced arthritis and the systemic immune response. 1834 15

In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA(+) T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.
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PMID:Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. 1945 Dec 63

The S100A4 protein is reported as a pivotal player in the tumor microenvironment with a metastasis-promoting function. Moreover, the upregulation of S100A4 is found in other non-malignant human disorders as cardiac and pulmonary systems and rheumatoid arthritis. In this study, we investigated the expression and significance of S100A4 in psoriasis. We found significant upregulation of S100A4 in the dermis of psoriatic skin compared with normal skin. This pattern of S100A4 expression differs considerably from that of other S100 proteins, S100A7 and S100A8/9, with predominant expression in the epidermis of psoriasis. Furthermore, we revealed a massive release of the biologically active forms of S100A4 from psoriatic skin. Interestingly, we found stabilization (increase) of p53 in the basal layer of epidermis in close proximity to cells expressing S100A4. To examine the possible implication of S100A4 in the pathogenesis of psoriasis, we analyzed the effect of S100A4 blocking antibodies in a human psoriasis xenograft SCID mouse model and observed a significant reduction of the epidermal thickness and impairment in cell proliferation and dermal vascularization. In conclusion, we showed strong upregulation and release of S100A4 in the upper dermis of psoriatic skin and found evidence indicating that S100A4 might actively contribute to the pathogenesis of psoriasis.
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PMID:Significance of the S100A4 protein in psoriasis. 1964 15


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