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)

Recent studies have shown that only breast cancer epithelial cells with intact p53 can induce metallothionein (MT) synthesis after exposure to metals. In this study, the potential role of p53 on regulation of MT was investigated. Results demonstrate that zinc and copper increased metal response elements (MREs) activity and MTF-1 expression in p53 positive MN1 and parental MCF7 cells. However, inactivation of p53 by treatment with pifithrin-alpha or the presence of inactive p53 inhibited MRE-dependent reporter gene expression in response to metals. MTF-1 levels remained unchanged after treatment with zinc in cells with nonfunctional p53. The introduction of wild-type p53 in MDD2 cells, containing nonfunctional p53, enhanced the ability of zinc to increase MRE-dependent reporter gene expression. The cellular level of p21Cip1/WAF1 was increased in MDD2 cells after p53 transfection, confirming the presence of active p53. The treatment of MN1 and parental MCF7 with trichostatin A led to a sixfold increase in the MRE activity in response to zinc. On the contrary, MRE activity remained unaltered in MDD2 cells with inactive p53. The above results demonstrate that activation of p53 is an important factor in metal regulation of MT.
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PMID:P53 mediated regulation of metallothionein transcription in breast cancer cells. 1747 70

Molecular interaction between p53 tumor suppressor and the copper protein azurin (AZ) has been demonstrated to enhance p53 stability and hence antitumoral function, opening new perspectives in cancer treatment. While some experimental work has provided evidence for AZ binding to p53, no crystal structure for the p53-AZ complex was solved thus far. In this work the association between AZ and the p53 DNA-binding domain (DBD) was investigated by computational methods. Using a combination of rigid-body protein docking, experimental mutagenesis information, and cluster analysis 10 main p53 DBD-AZ binding modes were generated. The resulting structures were further characterized by molecular dynamics (MD) simulations and free energy calculations. We found that the highest scored docking conformation for the p53 DBD-AZ complex also yielded the most favorable free energy value. This best three-dimensional model for the complex was validated by using a computational mutagenesis strategy. In this structure AZ binds to the flexible L(1) and s(7)-s(8) loops of the p53 DBD and stabilizes them through protein-protein tight packing interactions, resulting in high degree of both surface matching and electrostatic complementarity.
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PMID:Docking study and free energy simulation of the complex between p53 DNA-binding domain and azurin. 1770 63

Two new copper thiosemicarbazone complexes with an ONNS quadridentate system were synthesized and evaluated for anticancer activity on cisplatin-resistant neuroblastoma cells. Among these two copper complexes, the substituted 8-hydroxyquinoline-2-carboxaldehyde-4,4-dimethyl-3-thiosemicarbazide (CuHQDMTS) exhibited stronger cell growth inhibition activity than the unsubstituted copper 8-hydroxyquinoline-2-carboxaldehyde thiosemicarbazide complex (CuHQTS). Both CuHQTS and CuHQDMTS showed dose-dependent cell growth inhibition, cell cycle arrest and apoptosis induction activities on the SK-N-DZ neuroblastoma cells. Increased expression of p53 protein molecules was detected in the SK-N-DZ cells treated with CuHQTS. The data obtained in this study suggest that CuHQDMTS and CuHQTS hold potential as new, effective drugs for treatment of refractory neuroblastoma in children.
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PMID:Synthesis and characterization of new copper thiosemicarbazone complexes with an ONNS quadridentate system: cell growth inhibition, S-phase cell cycle arrest and proapoptotic activities on cisplatin-resistant neuroblastoma cells. 1790 66

Copper-64 (T(1/2) = 12.7 h; beta(+): 17.8%, beta(-): 41%) has applications in both positron emission tomography (PET) imaging and targeted radiotherapy of cancer. Copper-64 radiopharmaceuticals have shown tumor growth inhibition with a relatively low radiation dose in animal models; however, the mechanism of cytotoxicity has not been fully elucidated. Here, we report an investigation on the potential role of the tumor suppressor protein p53 in trafficking (64)Cu to tumor cell nuclei. Two EGFR expressing human colorectal cell lines (HCT 116 +/+ and HCT 116 -/-) that are positive or negative for p53 expression respectively, were used to compare internalization and nuclear localization of [(64)Cu]copper acetate and of (64)Cu-DOTA-cetuximab, a monoclonal anti-EGFR antibody. [(64)Cu]copper acetate uptake into cells was similar between the two cell lines during a 24 h time course. In contrast, the uptake of [(64)Cu]copper acetate in the nuclei of HCT 116 +/+ cells was significantly higher than in HCT 116 -/- cells (p < 0.0001) at 24 h. There was no difference in receptor binding, receptor-mediated internalization, and efflux of (64)Cu-DOTA-cetuximab between the two HCT 116 cells lines. However, nuclear localization of (64)Cu-DOTA-cetuximab showed increased uptake in the nuclei of HCT 116 +/+ cells as early as 4 h. These data demonstrate that (64)Cu is delivered to tumor cell nuclei in a p53 positive cell line in significantly greater amounts than in p53 negative cells by both non-specific and receptor-mediated uptake mechanisms.
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PMID:The role of p53 in the trafficking of copper-64 to tumor cell nuclei. 1793 76

Loss of intracellular neuronal glutathione (GSH) is an important feature of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The consequences of GSH depletion include increased oxidative damage to proteins, lipids, and DNA and subsequent cytotoxic effects. GSH is also an important modulator of cellular copper (Cu) homeostasis and altered Cu metabolism is central to the pathology of several neurodegenerative diseases. The cytotoxic effects of Cu in cells depleted of GSH are not well understood. We have previously reported that depletion of neuronal GSH levels results in cell death from trace levels of extracellular Cu due to elevated Cu(I)-mediated free radical production. In this study we further examined the molecular pathway of trace Cu toxicity in neurons and fibroblasts depleted of GSH. Treatment of primary cortical neurons or 3T3 fibroblasts with the glutathione synthetase inhibitor buthionine sulfoximine resulted in substantial loss of intracellular GSH and increased cytotoxicity. We found that both neurons and fibroblasts revealed increased expression and activation of p53 after depletion of GSH. The increased p53 activity was induced by extracellular trace Cu. Furthermore, we showed that in GSH-depleted cells, Cu induced an increase in oxidative stress resulting in DNA damage and activation of p53-dependent cell death. These findings may have important implications for neurodegenerative disorders that involve GSH depletion and aberrant Cu metabolism.
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PMID:Neurotoxicity from glutathione depletion is mediated by Cu-dependent p53 activation. 1804 46

The phytochemical resveratrol (RV) has become a focus of intense research owing to its roles in promoting longevity and in cancer prevention. As an anticancer agent, RV has primarily been linked to growth and death regulatory pathways. There is now growing evidence that, under physiological conditions, RV additionally contributes to the maintenance of genome stability. Thus, at the stage of DNA damage formation, RV protects the genome as an antioxidant via inhibition of inflammation, suppression of metabolic carcinogen activation, de novo expression of genes that encode detoxifying proteins and possibly even via radical scavenging properties. However, results demonstrating RV-dependent DNA breakage in the presence of Cu(II) ions and inhibition of DNA polymerases alpha and delta produced some controversy regarding RV's role as a caretaker compound. Significantly, recent studies have revealed that activation of ataxia telangiectasia mutated and ataxia telangiectasia Rad3 related could be a central effect of RV that underlies cell-cycle regulation and the newly described activation of fidelity control mechanisms in DNA double-strand break repair involving Nbs1 and p53. In this review, we discuss the existing data on RV's direct and indirect effects on genome integrity, in the light of future chemopreventive and chemotherapeutic protocols involving RV or related compounds.
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PMID:Take a break--resveratrol in action on DNA. 1817 51

Effective drugs are urgently needed for the treatment of advanced neuroblastoma refractory to conventional chemotherapy. Pyrrolidine dithiocarbamate (PDTC) is a copper-binding ligand, which showed cytotoxicity on many human tumor cells after binding with copper ions. In this study, we synthesized a copper-PDTC complex, which was characterized as a Cu(PDTC)2 complex, with elemental analyses (Fourier transform infrared, electrospray ionization mass spectra, and ultraviolet-visible spectroscopy). The Cu(PDTC)2 complex suppressed the proliferation of BE(2)C cells, a human neuroblastoma cell line, with an IC50 of 8.0 micromol/l, which was more potent than cisplatin (IC50 of 80 micromol/l). Treatment of BE(2)C cells with the Cu(PDTC)2 complex caused the S-phase arrest of cell cycle progression, cellular apoptosis, and necrosis, and increased the expression of p53 protein. The Cu(PDTC)2 complex holds potential as a new drug for the treatment of refractory neuroblastoma in children.
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PMID:Potent anticancer activity of pyrrolidine dithiocarbamate-copper complex against cisplatin-resistant neuroblastoma cells. 1817 8

The large-bite bis(phosphite) ligand [{(-OC(10)H(6)(mu-S)C(10)H(6)O-)P{mu-(-OC(10)H(6)(mu-S)C(10)H(6)O-)}P(-OC(10)H(6)(mu-S)C(10)H(6)O-)}] (Pinsertion markP) () was obtained by the reaction of PCl(3) and thiobis(2,2'-naphthol) (). The stoichiometric reactions of with elemental sulfur and selenium afforded the corresponding chalcogenide derivatives [(E)Pinsertion markP(E)] (, E = S; , E = Se) in good yield. Treatment of two equivalents of [ClAu(SMe(2))] with afforded a dinuclear complex [ClAu(Pinsertion markP)AuCl] (), whereas the 1 : 1 reaction with CuI yielded the [(Pinsertion markP)CuI] () complex. The copper(i) complex on treatment with various pyridyl derivatives, produced mixed-ligand complexes [(Pinsertion markP)CuI(NC(5)H(5))] (), [(Pinsertion markP)Cu(2,2'-bpy)]I (), [(Pinsertion markP)Cu(1,10-phen)]I () and {[(Pinsertion markP)Cu(4,4'-bpy)]I}(infinity) (). The compounds were tested for their cytotoxic activity on the human cervical cancer (HeLa) cell line. Compounds and were found to inhibit proliferation of HeLa cells significantly. These agents also induced apoptotic cell death in cancer cells. Evidence presented in this study indicated that the compounds and activate the tumor suppressor protein p53 in the colon adenocarcinoma (HCT-116) cell line.
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PMID:Large-bite bis(phosphite) ligand containing mesocyclic thioether moieties: synthesis, reactivity, group 11 (Cu(I), Au(I)) metal complexes and anticancer activity studies on a human cervical cancer (HeLa) cell line. 1841 53

Trace element deficiency or excess is implicated in the development or progression in some cancers. Here we report the elevated level of copper and low level of zinc in the plasma of esophageal cancer patients in Kashmir India--a high incidence area. The average level of copper was significantly higher (P < 0.0001) for patients than for controls, with a mean concentration of 169 microg/dl and 149 microg/dl for patients and controls, respectively. The control group consisted of 55 healthy individuals matched for age, sex, and place of residence of the patients. In contrast, the average level of zinc in patients was significantly lower than in controls (P < 0.0001), with a mean concentration of 86.8 microg/dl and 96.1 microg/dl for patients and controls, respectively. The levels of both copper and zinc showed significant differences based on gender and age in patients as compared to controls. Similarly, smokers depicted a significant increase in serum copper (N = 39, P = 0.002) and a decrease in serum zinc approaching level of significance in the patient group as compared to controls. The copper and zinc levels were significantly altered in patients (N = 40) when compared to controls as a function of snuff consumption. The differences in the levels of copper and zinc showed significant association with the consumption of local salted tea up to 1,500 ml per day, but the changes were insignificant beyond that. Patients with poorly differentiated tumors (N = 7) had a higher copper concentration than those with moderately or well-differentiated tumors (P < 0.0001). To validate the general notion that imbalance in copper and zinc levels may lead to higher prevalence of TP53 mutations, we compared the 3 variables, and no association was found between copper concentration and TP53 mutation status; but patients with TP53 mutant tumor had lower zinc levels than those with no mutation. In conclusion, our results point toward a role of the trace element imbalance in the esophageal tumorigenesis in high-risk Kashmiri population exposed to a range of nitroso compounds or their precursors. Further prospective cohort studies are warranted to determine whether change in the plasma zinc and copper homeostasis may represent an independent risk factor for this malignancy as well as a possible target for preventive intervention.
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PMID:Association between copper excess, zinc deficiency, and TP53 mutations in esophageal squamous cell carcinoma from Kashmir Valley, India--a high risk area. 1879 21

Apoptosis, also known as programmed cell death is a highly regulated and crucial process found in all multicellular organisms. It is not only implicated in regulatory mechanisms of cells, but has been attributed to a number of diseases, i.e. inflammation, malignancy, autoimmunity and neurodegeneration. A variety of toxins can induce apoptosis. Carcinogenic transition metals, viz. cadmium, chromium and nickel promote apoptosis along with DNA base modifications, strand breaks and rearrangements. Generation of reactive oxygen species, accumulation of Ca(2+), upregulation of caspase-3, down regulation of bcl-2, and deficiency of p-53 lead to arsenic-induced apoptosis. In the case of cadmium, metallothionein expression determines the choice between apoptosis and necrosis. Reactive oxygen species (ROS) and p53 contribute in apoptosis caused by chromium. Immuno suppressive mechanisms contribute in lead-induced apoptosis whereas in the case of mercury, p38 mediated caspase activation regulate apoptosis. Nickel kills the cells by apoptotic pathways. Copper induces apoptosis by p53 dependent and independent pathways. Beryllium stimulates the formation of ROS that play a role in Be-induced macrophage apoptosis. Selenium induces apoptosis by producing superoxide that activates p53. Thus, disorders of apoptosis may play a critical role in some of the most debilitating metal-induced afflictions including hepatotoxicity, renal toxicity, neurotoxicity, autoimmunity and carcinogenesis. An understanding of metal-induced apoptosis will be helpful in the development of preventive molecular strategies.
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PMID:Metals and apoptosis: recent developments. 1901 55


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