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

Zinc deficiency is characterized by an attenuation of growth factor signaling pathways and an amplification of p53 pathways. This outcome is facilitated by hypo-phosphorylation of AKT and ERK secondary to zinc deficiency, which are permissive events to the activation of the intrinsic cell death pathway. Low zinc concentrations provide an environment that is also conducive to the production of reactive oxygen/reactive nitrogen species (ROS/RNS) and caspase activation. Additionally, during zinc deficiency endogenous survival pathways such as NF-kappaB are inhibited in their transactivation potential. The above factors contribute to the irreversible commitment of the zinc deficient cell to death.
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PMID:Zinc deficiency-induced cell death. 1622 5

Nitric oxide (NO) is an unstable molecule with physiological and pathological properties. In brain, NO acts as a modulator of neurotransmission as well as a protector against neuronal death from several death stimuli. However, beside this protector effect, high NO concentrations produce neuronal death by a mechanism in which the caspase pathway is implicated. In this work, we demonstrate that in cortical neurons the NO toxicity is mediated by mitochondrial dysfunction. SNAP, an NO donor, induces apoptosis in these cells because it 1) increases the p53 and 2) induces cytochrome c release and activation of caspase-9 and caspase-3. SNAP also induces necrosis, through 1) breakdown of the mitochondrial membrane potential, 2) ATP decrease, 3) ROS formation, and 4) LDH and ATP release, indicative of oxidative stress and death by necrosis. To sum up, in cortical neurons, high NO concentrations produced cellular death by both an apoptotic and a necrotic mechanism in which the mitochondria are implicated.
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PMID:Mitochondrial involvement in nitric oxide-induced cellular death in cortical neurons in culture. 1639 99

Prothrombin is a plasma glycoprotein involved in blood coagulation and, as we have previously reported, prothrombin kringles inhibit BCE (bovine capillary endothelial) cell proliferation. To reveal the mechanism, we investigated the influence of rk-2 (recombinant human prothrombin kringle-2) on the BCE cell cycle progression and ROS (reactive oxygen species) generation using FACS (fluorescence-activated cell sorter) analysis. Cell cycle analysis showed a decrease of G(1) phase cells in cells treated with bFGF (basic fibroblast growth factor) and an increase in cells treated with rk-2, as compared with the control cells. But, the portion of the S phase was reversed. In Western blot analysis, bFGF induced cytoplasmic translocation of p21(Waf1/Cip1) and p27(Kip1) and phosphorylation of p27(Kip1) but rk-2 treatment inhibited translocation of p21(Waf1/Cip1) and p27(Kip1) from nucleus to cytoplasm and phosphorylation of p27(Kip1). Also, rk-2 induced up-regulation of p53 and nuclear p21(Waf1/Cip1) and inhibited the cyclin D1/CDK4 (cyclin-dependent kinase 4) complex. The ROS level of rk-2-treated BCE cells was increased 2-fold when compared with the control, but treatment with NAC (N-Acetyl-L: -cysteine), an anti-oxidant, decreased ROS generation about 55% as compared with the rk-2 treatment. NAC treatment also restored cell cycle progression inhibited by rk-2 and down-regulated p53 and nuclear p21(Waf1/Cip1) expression induced by rk-2.These data suggest that rk-2 induces the BCE cell cycle arrest at G(0)-G(1) phase through inhibition of the cyclin D1/CDK4 complex caused by increase of ROS generation and nuclear cyclin-dependent kinase inhibitors.
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PMID:Recombinant human prothrombin kringle-2 induces bovine capillary endothelial cell cycle arrest at G0-G1 phase through inhibition of cyclin D1/CDK4 complex: modulation of reactive oxygen species generation and up-regulation of cyclin-dependent kinase inhibitors. 1640 May 24

Our study focused on investigating the mechanism of action of estrogen in regulating p53 levels within osteoblasts. In the studies reported here, we attempted to understand the role of estrogen receptors, ER-alpha and ER-beta, in the regulation of p53 and osteoblast differentiation. We stably expressed ER-alpha and ER-beta in ROS 17/2.8 cells and isolated several single cell clones. These clones were initially characterized for expression of the exogenous receptors, and representative clones from each type were chosen for further analyses. Cell proliferation, alkaline phosphatase activity, and the viability of these clones in culture were tested. The cells expressing exogenous ER-alpha exhibited more differentiated characteristics than cells expressing ER-beta. Morphologically, ER-beta-overexpressing cells were more rounded than the ER-alpha-overexpressing cells, which were more elongated and fibroblastic in appearance. The ER-beta-expressing cells had a higher survival and growth rate when compared with ER-alpha cells. The ER-alpha clones were not as viable as ER-beta clones, and some of the ER-alpha cell lines showed signs of senescence, with an increase in senescence-associated (SA) galactosidase activity. The basal levels of p53 functional activity were higher in cells expressing ER-alpha as was protein expression of the p53-regulated gene p21. The significance of these receptors to osteoblast differentiation and p53 regulation is discussed.
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PMID:Effect of overexpression of estrogen receptors in osteoblasts. 1640 12

Hydrogen peroxide (H(2)O(2)), a representative ROS, has been used to study the apoptosis of cancer cells to oxidative stress. In this study, we exploited the cellular and molecular mechanisms involved in H(2)O(2)-induced apoptosis in human gastric carcinoma MGC803 cells. Exposure of cells to H(2)O(2) might cause significant viability loss and the increase in apoptotic rate. Treatment with 0.4 mmol/L H(2)O(2) up-regulated Bax but down-regulated Bcl-2 in a time-dependent manner, while Bcl-xL expression remained unchanged. Our results also showed that the levels of Fas and Fas-L were increased, the pro-caspase-3 and pro-caspase-9 were down-regulated in H(2)O(2)-treated MGC803 cells. Under H(2)O(2) stress, we found that the protein p53 also participated in MGC803 cells apoptosis. Taken together, the present study indicated that Fas-mediated cell surface death receptor pathway and mitochondria-mediated pathway may participate in regulating the MGC803 cells apoptosis under oxidative stress.
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PMID:Hydrogen peroxide-induced apoptosis in human gastric carcinoma MGC803 cells. 1653 11

Cellular prion protein (PrP(C)), a glycosylphosphatidylinositol-anchored membrane protein, was found in our lab to be widely expressed in gastric cancer cell lines. In order to evaluate its biological significance in human gastric cancer, we investigated its expression in a large series of gastric tissue samples (n = 124) by immuno histochemical staining with the monoclonal antibody 3F4. Compared with normal tissues, gastric adenocarcinoma showed increased PrP(C) expression, correlated with the histopathological differentiation (according to the WHO and Lauren classifications) and tumor progression (as documented by pTNM staging). To better understand the underlying mechanism, we introduced the PrP(C) and two pairs of RNAi into the poorly differentiated gastric cancer cell line AGS and found that PrP(C) suppressed ROS and slowed down apoptosis in transfected cells. Further study proved that the apoptosis-related protein Bcl-2 was upregulated whereas p53 and Bax were downregulated in the PrP(C)-transfected cells. A reverse effect was observed in PrP(C) siRNA-transfected cells. These results strongly suggested that PrP(C) might play a role as an effective antiapoptotic protein through Bcl-2-dependent apoptotic pathways in gastric cancer cells. Further study into the mechanism of these relationships might enrich the knowledge of PrP, better our understanding of the nature of gastric carcinoma, and further develop possible strategies to block or reverse the development of gastric carcinoma.
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PMID:Overexpression of PrPC and its antiapoptosis function in gastric cancer. 1658 85

We present evidence that pyrrolidine dithiocarbamate (PDTC) inhibits growth of p53-negative pancreatic adenocarcinoma cell lines via cell cycle arrest in the S-phase, while it has no effect on primary fibroblast proliferation. Growth inhibition of cancer cells is dependent on ROS and ERK1/2 induction as indicated by a significantly reduced PDTC-associated growth inhibition by the free radical scavenger N-acetyl-L-cysteine (NAC) or the MEK/ERK1/2 inhibitor (PD98059). Moreover, ERK1/2 induction is dependent on ROS production as demonstrated by a complete removal of PDTC-mediated ERK1/2 phosphorylation by NAC. p21(WAF1/CIP1) activation has a central role in growth inhibition by PDTC, as revealed by P21(WAF1/CIP1) silencing experiments with antisense oligonucleotide, and occurs via increased mRNA stability largely mediated by ROS/ERK induction. Conversely, PDTC does not affect P21(WAF1/CIP1) gene expression in primary fibroblasts, although it is able to activate p53 and the p53-regulated antioxidant SESN2. These results suggest that the resistance of fibroblasts to the cytotoxic action of PDTC may be related to the up-regulation of p53-dependent antioxidant genes. Finally, in vivo studies on PaCa44 cells subcutaneously xenografted in nude mice show that treatment with 100 or 200 mg/kg PDTC reduces of 30% or 60% the tumour volume, respectively, and does not cause any apparent form of toxicity.
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PMID:Increased stability of P21(WAF1/CIP1) mRNA is required for ROS/ERK-dependent pancreatic adenocarcinoma cell growth inhibition by pyrrolidine dithiocarbamate. 1690 5

Photodynamic therapy (PDT) is a novel and promising cancer treatment which employs a combination of a photosensitizing chemical and visible light to induce apoptosis in cancer cells. Singlet oxygen has been recognized as the main origin of oxidative stress in PDT. However, the precise mechanism of PDT-induced apoptosis is not well characterized, especially the dualistic role of nitric oxide (NO). To dissect the apoptosis pathways triggered by PDT, the intracellular free radicals in MCF-7 cells were investigated by examining a novel photosensitizer 2-butylamino-2-demethoxyhypocrellin B (2-BA-2-DMHB)-mediated PDT. It was found that exposure of the cells to 2-BA-2-DMHB and irradiation resulted in a significant increase of intracellular ROS in minutes, and then followed by cytoplasmic free calcium enhancement, mitochondrial nitric oxide synthase (mtNOS) activation, cytochrome c release, and apoptotic death. Scavengers of singlet oxygen or NO could attenuate PDT-induced cell viability loss, nucleus morphology changes, cytochrome c release, mitochondria swelling, and apo-apoptosis gene p53 and p21 mRNA levels. The results suggested that both ROS and NO played important roles in the apoptosis-induced by PDT.
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PMID:Mitochondrial reactive oxygen species and nitric oxide-mediated cancer cell apoptosis in 2-butylamino-2-demethoxyhypocrellin B photodynamic treatment. 1704 27

Non-steroidal anti-inflammatory drugs are well known to induce apoptosis of cancer cells independent of their ability to inhibit cyclooxygenase-2, but the molecular mechanism for this effect has not yet been fully elucidated. The purpose of this study was to elucidate the potential signaling components underlying sulindac-induced apoptosis in human multiple myeloma (MM) cells. We found that sulindac induces apoptosis by promoting ROS generation, accompanied by opening of mitochondrial permeability transition pores, release of cytochrome c and apoptosis inducing factor from mitochondria, followed by caspase activation. Bcl-2 cleavage and down-regulation of the inhibitor of apoptosis proteins (IAPs) family including cIAP-1/2, XIAP, and survivin, occurred downstream of ROS production during sulindac-induced apoptosis. Forced expression of survivin and Bcl-2 blocked sulindac-induced apoptosis. Most importantly, sulindac-derived ROS activated p38 mitogen-activated protein kinase and p53. SB203580, a p38 mitogen-activated protein kinase inhibitor, and RNA inhibition of p53 inhibited the sulindac-induced apoptosis. Furthermore, p53, Bax, and Bak accumulated in mitochondria during sulindac-induced apoptosis. All of these events were significantly suppressed by SB203580. Our results demonstrate a novel mechanism of sulindac-induced apoptosis in human MM cells, namely, accumulation of p53, Bax, and Bak in mitochondria mediated by p38 MAPK activation downstream of ROS production.
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PMID:Sulindac-derived reactive oxygen species induce apoptosis of human multiple myeloma cells via p38 mitogen activated protein kinase-induced mitochondrial dysfunction. 1713 20

Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-alpha), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67-74], we noticed many alterations in the cochlea. Histologically, at 4 weeks, intensive HIF-1alpha expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. Since oxygen radicals are required for the post-translational stabilization of HIF-1alpha during hypoxia, the tandem " HIF-ROS " induced multiple reactions within the cochlea, like a strong inflammatory response with increased expression of TNF-alpha, and inhibition of neuronal protection mechanisms with repression of IGF-1.
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PMID:Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea. 1714 99


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