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)

3-Nitrobenzanthrone (3-NBA) is an extremely potent mutagen in diesel exhaust. It is a lung carcinogen to rats, and therefore a suspected carcinogen to human. In order to clarify the mechanism of carcinogenicity of 3-NBA, we investigated oxidative DNA damage by N-hydroxy-3-aminobenzanthrone (N-OH-ABA), a metabolite of 3-NBA, using 32P-labeled DNA fragments from the human p53 tumor-suppressor gene. N-OH-ABA caused Cu(II)-mediated DNA damage, and endogenous reductant NADH dramatically enhanced this process. Catalase and a Cu(I)-specific chelator decreased DNA damage, suggesting the involvement of hydrogen peroxide (H2O2) and Cu(I). N-OH-ABA induced DNA damage at cytosine and guanine residues of ACG sequence complementary to codon 273, a well-known hot spot of the p53 gene. N-OH-ABA dose dependently induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation in the presence of Cu(II) and NADH. Treatment with N-OH-ABA increased amounts of 8-oxodG in HL-60 cells compared to the H2O2-resistant clone HP100, supporting the involvement of H2O2. The present study has demonstrated that the N-hydroxy metabolite of 3-NBA induces oxidative DNA damage through H2O2 in both a cell-free system and cultured human cells. We conclude that oxidative DNA damage may play an important role in the carcinogenic process of 3-NBA in addition to previously reported DNA adduct formation.
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PMID:Carcinogenic 3-nitrobenzanthrone induces oxidative damage to isolated and cellular DNA. 1654 93

We measured tumor-associated proteins (TAPs) and pollutants in blood, serum, and urine of 200 nonsmoking women 50-65 years of age, residing in the rural municipality of Peer or in Hoboken or Wilrijk, industrial suburbs of Antwerp, Belgium. Persons with occupational exposures or commuting to other towns were excluded. Residents from Hoboken had significantly higher levels of blood lead and serum zinc and polychlorinated biphenyls. Surprisingly, residents of Peer had significantly higher levels of serum cadmium, dioxin-like activity in blood fat, and urinary 1-hydroxypyrene. For 5 of the 12 TAPs assessed in this study, we observed significant differences in serum levels among residents of the three municipalities after adjusting for personal or lifestyle parameters. Although we found levels of internal exposure to pollutants to be quite homogeneous in Flanders, we found significantly higher levels of TAPs only in the industrial suburbs. In multiple regression with all 29 available personal, lifestyle, and internal exposure parameters, blood lead levels showed a positive association with serum levels of anti-p53, carcino-embryonic antigen (CEA), and tissue polypeptide-specific antigen (TPS) and with an index for mean TAP level (I(tap)); dioxin-like activity in serum and serum copper showed a positive association with serum CA 125 (cancer antigen 125); and serum zinc showed a positive association with serum levels of c-erbB-2 ectodomain and TPS. An index of internal exposure showed a positive association with serum levels of both CEA and anti-p53 and with I(tap). This study provides some evidence that levels of internal exposure such as those present in Flanders, in particular concerning lead, are indeed associated with biologic effects.
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PMID:Differences in tumor-associated protein levels among middle-age Flemish women in association with area of residence and exposure to pollutants. 1675 90

There is an association between occupational exposure to hair dyes and incidence of cancers. Permanent oxidant hair dyes are consisted of many chemical components including ortho-phenylenediamines. To clarify the mechanism of carcinogenesis by hair dyes, we examined DNA damage induced by mutagenic ortho-phenylenediamine (o-PD) and its derivatives, 4-chloro-ortho-phenylenediamine (Cl-PD) and 4-nitro-ortho-phenylenediamine (NO(2)-PD), using (32)P-labeled DNA fragments obtained from the human p16 and the p53 tumor suppressor gene. We also measured the content of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of oxidative DNA damage, in calf thymus DNA with an electrochemical detector coupled to a high performance liquid chromatograph. Carcinogenic o-PD and Cl-PD caused Cu(II)-mediated DNA damage, including 8-oxodG formation, and antioxidant enzyme superoxide dismutase (SOD) enhanced DNA damage. o-PD and Cl-PD caused piperidine-labile and formamidopyrimidine-DNA glycosylase-sensitive lesions at cytosine and guanine residues respectively in the 5'-ACG-3' sequence, complementary to codon 273, a well-known hotspot of the human p53 tumor suppressor gene. UV-vis spectroscopic studies showed that the spectral change of o-PD and Cl-PD required Cu(II), and addition of SOD enhanced it. This suggested that SOD enhanced the rate of Cu(II)-mediated autoxidation of o-PD and Cl-PD, leading to enhancement of DNA damage. On the other hand, mutagenic but non-carcinogenic NO(2)-PD induced no DNA damage. These results suggest that carcinogenicity of ortho-phenylenediamines is associated with ability to cause oxidative DNA damage rather than bacterial mutagenicity.
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PMID:Oxidative DNA damage induced by hair dye components ortho-phenylenediamines and the enhancement by superoxide dismutase. 1679 66

Although capsaicin exhibits antitumor activity, carcinogenic potential has also been reported. To clarify the mechanism for expression of potential carcinogenicity of capsaicin, we examined DNA damage induced by capsaicin in the presence of metal ion and various kinds of cytochrome P450 (CYP) using 32P-5'-end-labeled DNA fragments. Capsaicin induced Cu(II)-mediated DNA damage efficiently in the presence of CYP1A2 and partially in the presence of 2D6. CYP1A2-treated capsaicin caused double-base lesions at 5'-TG-3', 5'-GC-3' and CG of the 5'-ACG-3' sequence complementary to codon 273, a hotspot of p53 gene. DNA damage was inhibited by catalase and bathocuproine, a Cu(I) chelator, suggesting that reactive species derived from the reaction of H2O2 with Cu(I) participate in DNA damage. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine was significantly increased by CYP1A2-treated capsaicin in the presence of Cu(II). Therefore, we conclude that Cu(II)-mediated oxidative DNA damage by CYP-treated capsaicin seems to be relevant for the expression of its carcinogenicity.
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PMID:Mechanism of oxidative DNA damage induced by capsaicin, a principal ingredient of hot chili pepper. 1701 77

Tetranitromethane (TNM) is used as an oxidizer in rocket propellants and explosives and as an additive to increase the cetane number of diesel fuel. TNM was reported to induce pulmonary adenocarcinomas and squamous cell carcinomas in mice and rats. However, the mechanisms underlying carcinogenesis induced by TNM has not yet been clarified. We previously revealed that nitroTyr and nitroTyr-containing peptides caused Cu(II)-dependent DNA damage in the presence of P450 reductase, which is considered to yield nitroreduction. Since TNM is a reagent for nitration of Tyr in proteins and peptides, we have hypothesized that TNM-treated Tyr and Tyr-containing peptides induce DNA damage by the modification of Tyr. We examined DNA damage induced by TNM-treated amino acids or peptides using (32)P-5'-end-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. TNM-treated Tyr and Lys-Tyr-Lys induced DNA damage including the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine in the presence of Cu(II) and NADH. DNA damage was inhibited by catalase and bathocuproine, indicating the involvement of H(2)O(2) and Cu(I). The cytosine residue of the ACG sequence complementary to codon 273, well-known hotspots of the p53 gene, was cleaved with piperidine and Fpg treatments. On the other hand, nitroTyr and Lys-nitroTyr-Lys did not induce DNA damage in the presence of Cu(II) and NADH. Time-of-flight mass spectrometry confirmed that reactions between Lys-Tyr-Lys and TNM yielded not only Lys-nitroTyr-Lys but also Lys-nitrosoTyr-Lys. Therefore, it is speculated that the nitrosotyrosine residue can induce oxidative DNA damage in the presence of Cu(II) and NADH. It is concluded that Tyr-dependent DNA damage may play an important role in the carcinogenicity of TNM. TNM is a new type of carcinogen that induces DNA damage not by itself but via Tyr modification.
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PMID:Tyrosine-dependent oxidative DNA damage induced by carcinogenic tetranitromethane. 1704 Jan 8

[[trans-PtCl(NH(3))(2)](2)mu-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)-NH(2))(2))](4+) (BBR3464) is a cationic trinuclear platinum drug that is being evaluated in phase II clinical trials for treatment of lung and ovarian cancers. The structure and DNA binding profile of BBR3464 is different from drugs commonly used clinically. It is of great interest to evaluate the difference between the mechanisms of uptake employed by BBR3464 and cisplatin (c-DDP), as altered uptake may explain chemoresistance. Using transfected cell lines, we show that both c-DDP and BBR3464 use the copper transporter hCTR1 to enter cells and to a lesser extent, the ATP7B transporter to exit cells. Copper influenced c-DDP and BBR3464 uptake similarly; it increased the c-DDP and BBR3464 uptake in ovarian (A2780) and colorectal (HCT116) carcinoma cell lines as detected by ICP-OES. However, the effects of copper on c-DDP- and BBR3464-mediated cytotoxicity differed. Copper decreased c-DDP-induced apoptosis, caspase-3/7 activation, p53 induction and PARP cleavage in cancer cell lines. In contrast, copper increased BBR3464-induced apoptosis, and had little effect on caspase activation, PARP cleavage, and p53 induction. It was concluded that BBR3464 employs mechanisms of intracellular action distinct from c-DDP. Although these drugs use the same cellular transporters (hCTR1 and ATP7B) for influx and efflux, downstream effects are different for the two drugs. These experiments illustrate fundamental differences in the mechanisms of action between cisplatin and the novel Pt-based drug BBR3464.
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PMID:Differences in the cellular response and signaling pathways of cisplatin and BBR3464 ([[trans-PtCl(NH3)(2)]2mu-(trans-Pt(NH3)(2)(H2N(CH2)(6)-NH2)2)]4+) influenced by copper homeostasis. 1723 60

Dyslipidemia increases the risks for atherosclerosis in part by impairing endothelial integrity; endothelial progenitor cells (EPCs) play a pivotal role in reendothelialization. In this study, we investigated the mechanism whereby oxidized low-density lipoprotein (oxLDL) affects the function of differentiated EPCs (EDCs). In EDCs expanded in vitro from EPCs isolated from human cord blood, we measured EDC responses to both copper-oxidized LDL and L5, an electronegative LDL minimally oxidized in vivo in patients with hypercholesterolemia. OxLDL induced apoptosis of EDCs and impaired their response to nitric oxide. We found that the key to oxLDL-induced apoptosis in both EDCs and endothelial cells is the induction of a conformational change of Bax, leading to Bax activation without altering its expression. The conformationally changed Bax translocated to the mitochondria and stimulated apoptosis, as Bax knockdown prevented oxLDL-induced apoptosis in EDCs. The activation of Bax is mediated by an increase in p53 and knockdown of p53 abolished oxLDL-induced activation of Bax and apoptosis. OxLDL activated p53 through production of mitochondria-derived reactive oxygen species. In EDCs treated with a recombinant adenovirus expressing superoxide dismutase or N-acetyl-cysteine (but not catalase), the p53-Bax pathway activated by oxLDL was blocked, and apoptosis was prevented. Of importance, treatment of EDC with low-concentration L5 stimulated superoxide dismutase expression, which significantly attenuated apoptosis in EDCs exposed to high-concentration L5. These findings suggest that exposure of EDCs and endothelial cells to either experimentally prepared or naturally occurring modified LDL results in an increased transfer of mitochondria-derived superoxide anion to p53, which stimulates a conformational change in Bax favoring its translocation to the mitochondria with resultant apoptosis of these cells.
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PMID:Oxidized low-density lipoprotein stimulates p53-dependent activation of proapoptotic Bax leading to apoptosis of differentiated endothelial progenitor cells. 1728 42

We characterized the pro-apoptotic activity of two new synthesized isatin-Schiff base copper(II) complexes, obtained from isatin and 1,3-diaminopropane or 2-(2-aminoethyl)pyridine: (Cu(isapn)) and (Cu(isaepy)(2)), respectively. We demonstrated that these compounds trigger apoptosis via the mitochondrial pathway. The early induction of the p53/p21 system indicates a role for p53 in cell death, however, experiments carried out with small interfering RNA against p53, or with cells lacking p53, support that a p53-independent mechanism can also occur. The extent of apoptosis mirrors the kinetics of intracellular copper uptake. Particularly, Cu(isaepy)(2) enters the cells more efficiently and specifically damages nuclei and mitochondria, as evidenced by atomic absorption analysis of copper content and by the extent of nuclear and mitochondrial integrity. Conversely, Cu(isapn), although less permeable, induces a wide-spread oxidative stress, as demonstrated by analyses of reactive oxygen species concentration, and oxidation of proteins and lipids. The increase of the antioxidant defense, through the overexpression of Cu,Zn-SOD, partially counteracts cell death; whereas retinoic acid-mediated differentiation completely rescues cells from apoptosis induced by both compounds. The activation of JNK- and Akt-mediated phosphorylative pathways has been found to be not functional for apoptosis induction. On the contrary, apoptosis significantly decreased when the analogous zinc complex was used or when Cu(isaepy)(2) was incubated in the presence of a copper chelator. Altogether, our data provide evidence for a dual role of these copper(II) complexes: they are able to vehicle copper into the cell, thus producing reactive oxygen species, and could behave as delocalized lipophilic cation-like molecules, thus specifically targeting organelles.
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PMID:Pro-apoptotic activity of novel Isatin-Schiff base copper(II) complexes depends on oxidative stress induction and organelle-selective damage. 1732 30

The aim of this study was to evaluate the in vitro and in vivo effects of the new chemotherapy agent Casiopeina III-ia [(4,4'-dimethyl-2,2'-bipiridine)(acetylacetonate) Copper (II) nitrate] on HCT-15 (p53-/-) colon cellular line. In vitro, the drug reduced the viability and induced necrosis and apoptosis in a dose dependent manner, without affecting cell cycle phases. Apoptosis was related to Bax increasing levels, suggesting a caspase-dependent mechanism of death, as verified by nucleosomal fragmentation of DNA. In vivo, the antitumor activity of Casiopeina III-ia was tested in HCT-15 cells transplanted to nude mice. In this study we will show that the novel antineoplastic agent Casiopeina III-ia is active on this colon tumor line, setting out as a good candidate for the treatment of colon tumors refractory to chemotherapy.
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PMID:Casiopeina III-ia induces apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and has antitumor effect in vivo. 1739 Feb 15

Increasing evidence reveals the carcinogenicity of UVA radiation. We demonstrated that UVA-irradiated NADH induced damage to (32)P-labeled DNA fragments obtained from the p53 gene in the presence of Cu(II). Formamidopyrimidine glycosylase (Fpg)-sensitive lesions were formed at guanine residues, whereas piperidine-labile lesions occurred frequently at thymine residues. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), upon UVA exposure in the presence of Cu(II), increased depending on NADH concentration. Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of reactive species derived from H(2)O(2) and Cu(I). UVA-irradiated riboflavin induced DNA cleavage through electron transfer at 5' guanine of the 5'-GG-3' sequence with both Fpg and piperidine treatments; Fpg induced less cleavage at the guanine residues than piperidine. These results imply that NADH may participate as an endogenous photosensitizer in UVA carcinogenesis via H(2)O(2) generation, producing metal-mediated mutagenic lesions such as 8-oxodG.
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PMID:Photosensitized DNA damage induced by NADH: site specificity and mechanism. 1745 28


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