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)

Resveratrol is a naturally occurring polyphenol, which causes apoptosis in cultured cancer cells. We describe a cell surface resveratrol receptor on the extracellular domain of hetero-dimeric alphaVbeta3 integrin in MCF-7 human breast cancer cells. This receptor is linked to induction by resveratrol of extracellular-regulated kinases 1 and 2 (ERK1/2)- and serine-15-p53-dependent phosphorylation leading to apoptosis. The integrin receptor is near the Arg-Gly-Asp (RGD) recognition site on the integrin; an integrin-binding RGD peptide inhibits induction by resveratrol of ERK1/2- and p53-dependent apoptosis. Antibody (Ab) to integrin alphaVbeta3, but not to alphaVbeta5, inhibits activation by resveratrol of ERK1/2 and p53 and consequent apoptosis in estrogen receptor-alpha (ERalpha) positive MCF-7, and ERalpha-negative MDA-MB231 cells. Resveratrol is displaced from the purified integrin by an RGD, but not RGE, peptide, and by alphaVbeta3 integrin-specific Ab. Resveratrol action is blocked by siRNAbeta3, but not by siRNAalphaV. [14C]-Resveratrol binds to commercially purified integrin alphaVbeta3 and to alphaVbeta3 prepared from MCF-7 cells; binding of [14C]-resveratrol to the beta3, but not to the alphaV monomer, is displaced by unlabeled resveratrol. In conclusion, binding of resveratrol to integrin alphaVbeta3, principally to the beta3 monomer, is essential for transduction of the stilbene signal into p53-dependent apoptosis of breast cancer cells.
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PMID:Integrin alphaVbeta3 contains a receptor site for resveratrol. 1679 May 23

Ochnaflavone (c-3 of apigenin-0-c-4 of apigenin; OC), a biflavonoid present in the human diet, is known to inhibit angiotensin II-induced hypertrophy and serum-induced smooth muscle cell proliferation. OC is known to have anti-fungal and anti-inflammatory activities. However, it is not known whether OC exerts similar cardioprotective effects in cells treated with tumor necrosis factor (TNF)-alpha. In this study, we isolated OC from Lonicera japonica and studied its effect on matrix metalloproteinase-9 (MMP-9) gene expression in human aortic smooth muscle cells (HASMC). Furthermore, we investigated whether OC exerts the multiple suppressive effects on cytokine TNF-alpha-induced HASMC. Treatment of OC showed its potent inhibitory effects on DNA synthesis of cultured HASMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and G1 cell cycle arrest. Treatment of OC, which induced a cell cycle block in G1-phase, induced downregulation of cyclins and CDKs and upregulation of the CDK inhibitor p21(waf1) expression, whereas upregulation of p27 or p53 by OC was not observed. Because anti-atherogenic effects need not be limited to anti-proliferation, we decided to examine whether OC exerts inhibitory effects on MMP-9 activity in TNF-alpha-induced HASMC. OC inhibited TNF-alpha-induced MMP-9 secretion on HASMC in a dose-dependent manner. This inhibition was characterized by downregulation of MMP-9, which was transcriptionally regulated at nuclear factor (NF)-kappaB site and activation protein (AP)-1 site in the MMP-9 promoter. These findings indicate the efficacy of OC in inhibiting cell proliferation, G1 to S-phase cell cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 on TNF-alpha-induced HASMC. The findings of the present study may provide a potential mechanism that explains the anti-atherogenic activity of OC.
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PMID:Ochnaflavone inhibits TNF-alpha-induced human VSMC proliferation via regulation of cell cycle, ERK1/2, and MMP-9. 1679 41

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

The effect of Zn on p53-independent cell death was examined in IIC9 embryonic fibroblasts. Despite the fact that these cells are p53-minus, Zn-mediated death occurs via an apoptotic mechanism. Death is facilitated by the presence of the Zn ionophore, pyrithione, indicating that intracellular Zn initiates the death response. Our investigations of the mechanism of Zn action demonstrate that Zn induces the death of IIC9 cells in a manner that is ERK-dependent. Expression of dn-(dominant negative)Ras attenuates ERK1/2 activation by Zn, and correspondingly reduces its cytotoxic effects. Raf-RBD pull-down experiments confirm that Zn treatment activates Ras and identified H-Ras as the specific isoform activated. This contrasts the activation of N-Ras that occurs when IIC9 cells are stimulated with thrombin. Thus, although the prolonged activation of the Ras/ERK pathway by Zn is similar to that seen when induced by mitogen, the distinguishing feature appears to be the isoform specificity of Ras activation.
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PMID:Zinc induces ERK-dependent cell death through a specific Ras isoform. 1701 54

Extracellular signal-regulated kinase (ERK)1/2 activity is reported to be required in mammalian cells for timely entry into and exit from mitosis (i.e., the G2-mitosis [G2/M] and metaphase-anaphase [M/A] transitions). However, it is unclear whether this involvement reflects a direct requirement for ERK1/2 activity during these transitions or for activating gene transcription programs at earlier stages of the cell cycle. To examine these possibilities, we followed live cells in which ERK1/2 activity was inhibited through late G2 and mitosis. We find that acute inhibition of ERK1/2 during late G2 and through mitosis does not affect the timing of the G2/M or M/A transitions in normal or transformed human cells, nor does it impede spindle assembly, inactivate the p38 stress-activated checkpoint during late G2 or the spindle assembly checkpoint during mitosis. Using CENP-F as a marker for progress through G2, we also show that sustained inhibition of ERK1/2 transiently delays the cell cycle in early/mid-G2 via a p53-dependent mechanism. Together, our data reveal that ERK1/2 activity is required in early G2 for a timely entry into mitosis but that it does not directly regulate cell cycle progression from late G2 through mitosis in normal or transformed mammalian cells.
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PMID:Extracellular signal-regulated kinase 1/2 activity is not required in mammalian cells during late G2 for timely entry into or exit from mitosis. 1703 35

The aim of this study was to investigate the inhibitory effect of non-aglycone cyanidin on TNF-alpha-induced endothelial cell apoptosis and its mechanism through enhancing expression of thioredoxin in endothelial cells. We found that exposure of the serum-starved BAECs to TNF-alpha increased significantly the number of dead cells, the cleaved caspase-3 and cleaved poly(ADP-ribose)polymerase (RARP)assayed by Western blot, whereas supplementation with cyanidin considerably suppressed these events. Inhibitors of the Akt, ERK1/2, Src kinase and transfection with a dominant-negative Akt cDNA blocked the inhibitory effect of cyanidin on cleaved caspase-3. Cyanidin significantly elevated expression of endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx). The increased Trx expression was blocked by siRNA transfection of cGMP-dependent protein kinase (PKG) and by using a PKG inhibitor, KT5823. Cyanidin also ameliorated TNF-alpha-induced decrease of Trx S-nitrosylation and intracellular glutathione and elevation of 4-hydroxynonenal (4-HNE), a major aldehydic product of lipid peroxidation. Furthermore, cyanidin also restored S-nitrosylation of caspase-3 and reduced the rise in expression and acetylation of tumor suppression gene p53. However, KT5823 or L-NAME, an inhibitor of eNOS, removed the preventive effects of cyanidin. Our data show that inhibitory effect of cyanidin on TNF-alpha-induced apoptosis involves multiple pathways, such as Akt activation, eNOS and thioredoxin expression in endothelial cells.
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PMID:Inhibitory effect of polyphenol cyanidin on TNF-alpha-induced apoptosis through multiple signaling pathways in endothelial cells. 1704 69

We have recently shown that the expression levels of both cannabinoid receptors CB(1) and CB(2) are higher in human prostate cancer cells than in normal prostate epithelial cells, and treatment of LNCaP cells with WIN-55,212-2 (a mixed CB(1)/CB(2) agonist) resulted in inhibition of cell growth and induction of apoptosis (Sarfaraz, S., Afaq, F., Adhami, V. M., and Mukhtar, H. (2005) Cancer Res. 65, 1635-1641). This study was conducted to understand the mechanistic basis of these effects. Treatment of LNCaP cells with WIN-55,212-2 (1-10 microm; 24 h) resulted in: (i) an arrest of the cells in the G(0)/G(1) phase of the cell cycle; (ii) an induction of p53 and p27/KIP1; (iii) down-regulation of cyclins D1, D2, E; (iii) decrease in the expression of cdk-2, -4, and -6; (iv) decrease in protein expression of pRb; (v) down-regulation of E2F (1-4); and (vi) decrease in the protein expression of DP1 and DP2. Similar effects were also observed when androgen-independent PC3 cells were treated with WIN-55,212-2 (5-30 microm). We further observed sustained up-regulation of ERK1/2 and inhibition of PI3k/Akt pathways in WIN-55,212-2-treated cells. Inhibition of ERK1/2 abrogated WIN-55,212-2-indued cell death suggesting that sustained activation of ERK1/2 leads to cell cycle dysregulation and arrest of cells in G(0)/G(1) phase subsequently leading to an induction of apoptosis. Further, WIN-55,212-2 treatment of cells resulted in a dose-dependent increase in Bax/Bcl-2 ratio in such a way that favors apoptosis. The induction of apoptosis proceeded through down-regulation of caspases 3, 6, 7, and 9 and cleavage of poly (ADP-ribose) polymerases. Based on these data we suggest that cannabinoid receptor agonists should be considered as novel agents for the management of prostate cancer.
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PMID:Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest. 1706 43

DNA damage is known to be an initiator of neuronal death in neurodegenerative conditions such as Parkinson's and Alzheimer's diseases. The mechanism linking DNA damage and neuronal death is not completely understood. Here, we delineate the mechanism by which neuronal death evoked by DNA damage is controlled. Using mouse cortical neurons and SH-SY5Y human neuroblastoma cells, we identify a critical role of ERK signaling in neuronal death induced by DNA damage upon mitomycin C treatment. In addition, we provide evidence that the ERK signaling regulates Cyclin-dependent kinase 5 (Cdk5) activity and stability of tumor suppressor p53. Mitomycin C increased expression of p35, a specific activator of neuronal Cdk5 in an ERK1/2-dependent manner. Moreover, stability of p53 was increased by its phosphorylation on Ser33 and Ser46 by Cdk5, leading to neuronal death. Finally, we show that activated ERK induced increased expression of the Egr-1 transcription factor, which then bound to the promoter region of p35. We suggest subsequent increase of p35 expression and Cdk5 activity contribute to p53-dependent neuronal death. Thus, the present finding provides a new insight into a molecular mechanism underlying DNA damage-induced neuronal death.
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PMID:Regulation of cyclin-dependent kinase 5 and p53 by ERK1/2 pathway in the DNA damage-induced neuronal death. 1711 79

UV light excites aromatic residues, causing these to disrupt nearby disulphide bridges. The EGF receptor is rich in aromatic residues near the disulphide bridges. Herein we show that laser-pulsed UV illumination of two different skin-derived cancer cell lines i.e. Cal-39 and A431, which both overexpress the EGF receptor, leads to arrest of the EGFR signaling pathway. The phosphorylation status of the receptor and the level of phosphorylated downstream signaling molecules i.e. AKT and the mitogen activated protein kinases (MAPKs) ERK1 and 2 is detected by Western blotting using phosphospecific antibodies. There was a threshold level, below which the receptor could not be blocked. In addition, illumination caused the cells to upregulate the cyclin-dependent kinase inhibitor p21WAF1, irrespective of the p53 status. Since the EGF receptor is often overexpressed in cancers and other proliferative skin disorders, it might be possible to significantly reduce the proliferative potential of these cells making them good targets for laser-pulsed UV light treatment.
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PMID:UV light blocks EGFR signalling in human cancer cell lines. 1714 27

One of the earliest descriptions of non-neuronal ACh synthesis was by Morris who reported that ACh was synthesized in the placenta [1]; furthermore, Falugi et al. showed the presence of AChE in human fibrosarcoma cells [2]. Afterward, the expression of ACh, AChE, and cholinergic receptors in non-neuronal cells was reported in several studies [3-16]. Indeed, recent data reported that SCLC expresses a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumours [16]. Moreover, it has been recently reported that nicotine in lung adenocarcinoma A549 cells, potently induces Bad phosphorylation at serine (S)112, S136 and S155 in a mechanism involving activation of MAPKs, ERK1/2, PI3K/AKT and PKA through the linking to alpha7-receptors [9]. Bad phosphorylation results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol [9]. We have recently reported that human malignant pleural mesothelioma expresses a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) have a proliferative effect and antagonists (i.e. curare or alpha-cobratoxin) have an inhibitory effect. Furthermore apoptosis mechanisms are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-kappaB complexes and phosphorylation of Bad at S112, curare proapoptotic via G0-G1 arrest p21waf-1-dependent, but p53-independent) [16]. The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and opens up new translational research strategies.
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PMID:Development of novel therapeutic strategies for lung cancer: targeting the cholinergic system. 1716 19


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