UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-kappaB activity. Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.
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PMID:Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. 1756 14

Resveratrol (RES) is a natural occurring phytoalexin that has been shown to have chemopreventive activity. Resveratrol acts both by suppressing cell proliferation and inducing apoptosis in a variety of cancer cell lines. In this study, we show that RES induces apoptosis in MOLT-4 acute lymphoblastic leukaemia cells by modulating three different pathways that regulate cells survival and cell death. We show for the first time that RES inhibits the survival signalling pathways Notch and their down stream effector and modulates the operation of interacting signalling systems. It induces an increase in the levels of the pro-apoptotic proteins p53, its effector p21waf and Bax. We also show that RES inhibits the PI3K/Akt pathway and activates Gsk-3beta. The data presented here demonstrate unequivocally that RES induces apoptosis by inhibiting the Notch pathway and markedly influencing the operation of the interacting apoptosis pathways mediated by p53 and PI3K/Akt. These data support findings from other laboratories that have suggested the use of RES as a chemopreventive agent. Here, we have identified potential signalling pathways influenced by RES and this could lead to the identification of the targets of RES-induced apoptosis and growth control.
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PMID:Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. 1786 49

The inflammatory process plays a pivotal role during the pathogenesis of osteoarthritis, dominated by catabolic processes initiated by pro-inflammatory cytokines such as IL-1beta. Resveratrol, a natural phytoalexin occurring in various fruits has previously been shown to exhibit anti-inflammatory properties in several cell types. We investigated, whether resveratrol may be a useful blocker of pro-inflammatory cytokine signalling pathways in arthritis. We first examined the effects of resveratrol on the proliferation and production of IL-1beta in primary human articular chondrocytes treated with IL-1betain vitro. Resveratrol reversed significantly IL-1beta-reduced cell proliferation and blocked IL-1beta-stimulated cell membrane bound- and mature IL-1beta synthesis in chondrocytes. Furthermore, resveratrol was able to inhibit the IL-1beta-induced degradation of mitochondria and apoptosis in chondrocytes in a time-dependent manner. Because caspase inhibitor Z-DEVD-FMK abolished the IL-1beta-induced apoptosis in chondrocytes, we examined the effect of resveratrol on the caspase pathway and found that resveratrol blocked the cysteine protease caspase-3 and subsequent cleavage of the DNA repair enzyme PARP. Additionally, resveratrol reversed the IL-1beta-induced up-regulation of reactive oxygen species (ROS) in chondrocytes. Finally, we show that resveratrol induced ubiquitin-independent degradation of tumor suppressor gene protein p53 and inhibited p53-induced apoptosis in chondrocytes in a dose-dependent manner. Our results indicate that resveratrol seems to be an effective in vitro anti-inflammatory agent and has a chondroprotective capacity through suppression of (1) IL-1beta- (2) ROS- and (3) tumor suppressor protein p53-production. Further studies should be undertaken to define a possible implication of resveratrol in osteoarthritis therapy and cartilage tissue engineering.
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PMID:Regulation of inflammation signalling by resveratrol in human chondrocytes in vitro. 1795 54

Within the hierarchy of epithelial stem cells, normal progenitor cells may express regulated telomerase during renewal cycles of proliferation and differentiation. Discontinuous telomerase activity may promote increased renewal capacity of progenitor cells, while deregulated/continuous telomerase activity may promote immortalization when differentiation and/or senescent pathways are compromised. In the present work, we show that resveratrol activates, while progesterone inactivates, continuous telomerase activity within 24 h in subpopulations of human Li-Fraumeni syndrome-derived breast epithelial cells. Resveratrol results in immortalization of mixed progenitor cells with mutant p53, but not human epithelial cells with wild type p53. Our results demonstrate the potential for renewing progenitor cells with mutant p53 to immortalize after continuous telomerase expression when exposed to certain environmental compounds. Understanding the effects of telomerase modulators on endogenous telomerase activity in progenitor cells is relevant to the role of immortalization in the initiation and progression of cancer subtypes.
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PMID:Immortalization of epithelial progenitor cells mediated by resveratrol. 1796 19

Resveratrol, a natural phytoestrogen found in red wine and a variety of plants, is reported to have protective effects against lung cancer; however, there is little work directed toward the understanding of the mechanism of its action in this disease. In this study, we used a combination of experimental approaches to understand the biological activity and molecular mechanisms of resveratrol. Microarray gene expression profiling and high-throughput immunoblotting (PowerBlot) methodologies were employed to gain insights into the molecular mechanisms of resveratrol action in human lung cancer cells. In this report, we confirm the up-regulation of p53 and p21 and the induction of apoptosis by the activation of the caspases and the disruption of the mitochondrial membrane complex. We show the arrest of A549 cells in the G(1) phase of cell cycle in the presence of resveratrol and also report alterations in both gene and protein expressions of cyclin A, chk1, CDC27, and Eg5. Furthermore, the results indicated that resveratrol action is mediated via the transforming growth factor-beta pathway, particularly through the Smad proteins. Results showed the down-regulation of the Smad activators 2 and 4 and the up-regulation of the repressor Smad 7 as a result of resveratrol treatment. Resveratrol is a potent inhibitor of A549 lung cancer cell growth, and our results suggest that resveratrol may be a promising chemopreventive or chemotherapeutic agent for lung cancer.
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PMID:Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. 1808 32

Resveratrol (RV) inhibits tumour initiation, promotion and progression which has mainly been explained by its properties in cell cycle control and apoptosis induction. So far, ambiguous observations have been published regarding its influence on genomic stability. To study RV's effects on DNA double-strand break (DSB) repair, we applied the established enhanced green fluorescent protein (EGFP)- and I-SceI-based assay system on RV-treated lymphoblastoid cell lines (LCLs). We show that RV inhibits both, homologous recombination (HR) and non-homologous end joining (NHEJ) independently of its known growth and death regulatory functions. Using (i) the isogenic cell lines TK6 and WTK1, which differ in their p53 status, (ii) LCLs from patients with ataxia telangiectasia, (iii) shRNA-mediated p53 knockdown and (iv) chemical inhibition of ATM/ATR by caffeine, we established an ATM-p53-dependent pathway of HR inhibition by RV. Additional use of LCLs from Nijmegen breakage syndrome patients furthermore provided evidence for an ATM/ATR-Nbs1-dependent inhibition of microhomology-mediated NHEJ after RV treatment. We propose that activation of ATM and/or ATR is a central effect of RV. Repression of error-prone recombination subpathways could at least partially explain the chemopreventive effects of this natural plant constituent in animal cancer models.
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PMID:Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53- and -Nbs1-dependent manner. 1817 44

Resveratrol has been reported to have a wide variety of biological effects. However, little is known regarding its role on phosphorylation of histone H3, MAP kinase p38, SIR2 and p53 in type I diabetic nephropathy (DN). Hence, the present study was undertaken to examine changes in the above said parameters by resveratrol treatment. Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg/kg, i.p.). DN was assessed by measurements of blood urea nitrogen and creatinine levels. Phosphorylation of histone H3, SIR2, p53 and MAP kinase p38 expression were examined by western blotting. This study reports that treatment of resveratrol prevents the decrease in the expression of SIR2 in diabetic kidney. It also prevents increase in p38, p53 expression and dephosphorylation of histone H3 in diabetic kidney. This is the first report which suggests that protection against development of diabetic nephropathy by resveratrol treatment involves change in phosphorylation of histone H3, expression of Sir-2, p53 and p38 in diabetic kidney.
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PMID:Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy. 1840 39

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

Cyclooxygenase-2 (COX-2) content is increased in many types of tumor cells. We have investigated the mechanism by which resveratrol, a stilbene that is pro-apoptotic in many tumor cell lines, causes apoptosis in human head and neck squamous cell carcinoma UMSCC-22B cells by a mechanism involving cellular COX-2. UMSCC-22B cells treated with resveratrol for 24 h, with or without selected inhibitors, were examined: (1) for the presence of nuclear activated ERK1/2, p53 and COX-2, (2) for evidence of apoptosis, and (3) by chromatin immunoprecipitation to demonstrate p53 binding to the p21 promoter. Stilbene-induced apoptosis was concentration-dependent, and associated with ERK1/2 activation, serine-15 p53 phosphorylation and nuclear accumulation of these proteins. These effects were blocked by inhibition of either ERK1/2 or p53 activation. Resveratrol also caused p53 binding to the p21 promoter and increased abundance of COX-2 protein in UMSCC-22B cell nuclei. Resveratrol-induced nuclear COX-2 accumulation was dependent upon ERK1/2 activation, but not p53 activation. Activation of p53 and p53-dependent apoptosis were blocked by the COX-2 inhibitor, NS398, and by transfection of cells with COX-2-siRNA. In UMSCC-22B cells, resveratrol-induced apoptosis and induction of nuclear COX-2 accumulation share dependence on the ERK1/2 signal transduction pathway. Resveratrol-inducible nuclear accumulation of COX-2 is essential for p53 activation and p53-dependent apoptosis in these cancer cells.
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PMID:Resveratrol causes COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer cells. 1844 86

The incidence of melanoma continues to dramatically increase in most Western countries with predominantly Caucasian populations. However, only limited therapies for the metastatic stage of the disease are currently available. The main purpose of this study is to determine approaches that can substantially increase radiosensitivity of melanoma cells. The PI3K-AKT, NF-kappaB and COX-2 pathways, which are involved in the radioprotective response, are highly active in melanoma cells. Pharmacological suppression of COX-2 and PI3K-AKT, or RNAi-mediated knockdown of COX-2, substantially increased levels of G2/M arrest of the cell cycle and decreased clonogenic survival of gamma-irradiated melanomas, predominantly via a necrotic mechanism. On the other hand, resveratrol, a polyphenolic phytoalexin, selectively targets numerous cell signaling pathways, decreasing clonogenic survival primarily via an apoptotic mechanism. In melanoma cells, resveratrol inhibits STAT3 and NF-kappaB-dependent transcription, culminating in suppression of cFLIP and Bcl-xL expression, while activating the MAPK- and the ATM-Chk2-p53 pathways. Resveratrol also upregulates TRAIL promoter activity and induces TRAIL surface expression in some melanoma cell lines, resulting in a rapid development of apoptosis. Sequential treatment of melanoma cells, first with gamma-irradiation to upregulate TRAIL-R surface expression, and then with resveratrol to suppress antiapoptotic proteins cFLIP and Bcl-xL and induce TRAIL surface expression, had dramatic effects on upregulation of apoptosis in some melanoma lines, including SW1 and WM35. However, for melanoma lines exhibiting suppressed translocation of TRAIL to the cell surface, a necrotic mechanism of cell death was primarily involved in radiation response. Hence, surface expression of TRAIL induced by resveratrol appears to be a decisive event, one which determines an apoptotic versus a necrotic response of melanoma cells to sequential treatment.
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PMID:Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival. 1845 17

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