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)

Hexavalent chromium [Cr(VI)] is a known etiological factor in human lung cancer. Cr(VI) exposure-related lung cancer has a high mutation incidence in the p53 gene. Upon intake in human cells Cr(VI) is reduced to Cr(III), which is able to conjugate with amino acids and consequently form either binary Cr(III)-DNA or ternary Cr(III)-amino acid-DNA adducts. Both binary and ternary Cr(III)-DNA adducts are mutagenic. We have found that the Escherichia coli nucleotide excision enzyme UvrABC nuclease is able to incise Cr(III)- and Cr(III)-histidine-modified plasmid DNA and the extent of incision is proportional to the amount of Cr(III)-DNA adducts in the plasmid. In order to determine the role of Cr(III)-DNA adducts in the mutagenesis of the p53 gene in human cancer using the UvrABC nuclease incision method, we have mapped the Cr(III)-DNA distribution in PCR DNA fragments amplified from exons 5, 7 and 8 of the p53 gene. We have found that the sequence specificities of Cr(III)-DNA and Cr(III)-histidine-DNA adducts in the p53 gene sequence are identical and that both types of adducts are preferentially formed at -NGG- sequences, including codons 245, 248 and 249, the mutational hotspots in human lung cancer. It has been found that Cr(III)-DNA adducts induce mainly G to T mutations. Therefore, these results suggest that Cr(III)-DNA adduct formation contributes to the p53 gene mutations in lung carcinogenesis.
 ...
PMID:Sequence specificity of Cr(III)-DNA adduct formation in the p53 gene: NGG sequences are preferential adduct-forming sites. 1625 Dec 6

Certain hexavalent chromium [Cr(VI)] compounds are known genotoxic respiratory carcinogens, which induce apoptosis as a predominant mode of cell death. Selection of cells that are resistant to apoptosis may be a factor in tumour progression. We developed sub-populations of telomerase-transfected human fibroblasts (BJ-hTERT) that survived a 99% clonogenically lethal exposure to Cr(VI) (B-5Cr). B-5Cr cells were markedly resistant to apoptosis induced by several agents and exhibited increased clonogenic survival, especially at apoptogenic doses. B-5Cr cells did not exhibit altered cellular uptake of Cr(VI) and retained a normal p53 response to Cr(VI) exposure. We conducted large-scale gene expression analysis at different time-points after a secondary genotoxic Cr(VI) insult in B-5Cr and BJ-hTERT cells using Affymetrix Genechip human genome arrays. Cr(VI) exposure led to differential regulation of many genes, which affect a diverse set of cellular activities such as transcription, signal transduction, stress response, cell adhesion, DNA repair, apoptosis and cell cycle modulation. We compared Cr(VI)-induced altered gene expression in the B-5Cr cells to that in the parental cells and identified 223, 147 and 204 genes with at least a two-fold difference in expression at 4, 8 and 18 h after exposure, respectively. Cluster analysis by gene function revealed altered expression of genes involved in apoptosis, cell cycle regulation and DNA repair. Our data suggest an alteration in gene expression that may favor cell survival and/or incomplete DNA repair after genotoxic exposure. Selection of cells with altered expression of these genes may constitute the early stages of tumour progression.
 ...
PMID:Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure. 1628 27

Hexavalent chromium compounds are well-documented human carcinogens. In vitro experiments show Cr (VI) induces cell death by apoptosis by activating p53 protein. The aim of this study was to evaluate Cr (VI)-induced apoptosis in a human bronchial epithelial cell line (BEAS-2B) and in a lymphoblastic leukemia cell line (MOLT-4). Cr (VI) caused a dose- and time-dependent increase in the apoptosis rate in both cell lines. Western blotting showed increased p53 protein expression in MOLT-4 cells, but not in BEAS-2B cells, after exposure to 0.5 and 3 muM hexavalent chromium for 12 hours and 4 hours, respectively. Apoptotic cell death induced by Cr (VI) was not decreased by pretreatment with caspase-3, -8, and -9 inhibitors. These preliminary results provide evidence of Cr (VI)-induced apoptosis, which deserves further investigation in occupationally exposed workers.
 ...
PMID:Chromium VI-induced apoptosis in a human bronchial epithelial cell line (BEAS-2B) and a lymphoblastic leukemia cell line (MOLT-4). 1653 37

Several studies have demonstrated that zinc is required for the optimal functioning of the skin. Changes in intracellular zinc concentrations have been associated with both improved protection of skin cells against various noxious factors as well as with increased susceptibility to external stress. Still, little is known about the role of intracellular zinc in hexavalent chromium (Cr(VI))-induced skin injury. To address this question, the effects of zinc deficiency or supplementation on Cr(VI)-induced cytotoxicity, oxidative stress, DNA injury and cell death were investigated in human diploid dermal fibroblasts during 48 h. Zinc levels in fibroblasts were manipulated by pretreatment of cells with 100 microM ZnSO4 and 4 or 25 microM zinc chelator TPEN. Cr(VI) (50, 10 and 1 microM) was found to produce time- and dose-dependent cytotoxicity resulting in oxidative stress, suppression of antioxidant systems and activation of p53-dependent apoptosis which is reported for the first time in this model in relation to environmental Cr(VI). Increased intracellular zinc partially attenuated Cr(VI)-induced cytotoxicity, oxidative stress and apoptosis by enhancing cellular antioxidant systems while inhibiting Cr(VI)-dependent apoptosis by preventing the activation of caspase-3. Decreased intracellular zinc enhanced cytotoxic effects of all the tested Cr(VI) concentrations, leading to rapid loss of cell membrane integrity and nuclear dispersion--hallmarks of necrosis. These new findings suggest that Cr(VI) as a model environmental toxin may damage in deeper regions residing skin fibroblasts whose susceptibility to such toxin depends among others on their intracellular Zn levels. Further investigation of the impact of Zn status on skin cells as well as any other cell populations exposed to Cr(VI) or other heavy metals is warranted.
 ...
PMID:The role of intracellular zinc in chromium(VI)-induced oxidative stress, DNA damage and apoptosis. 1688 9

The toxicity of cadmium, lead, chromium, and arsenite on Caenorhabditis elegans was investigated to identify sensitive biomarkers for environmental monitoring and risk assessment. Effects of these metals on stress-related gene expression, growth, reproduction, and mortality of C. elegans were investigated under laboratory conditions. The possibility of using C. elegans as a biosensor for environmental toxicity monitoring was also tested using a green fluorescent protein transgenic nematode. The 24-h median lethal concentrations of cadmium, lead, chromium, and arsenite in C. elegans were 846, 34, 115, and 92 mg/L, respectively. Cadmium exposure led to an increase in the expression of most of the genes tested. The degree of increase was more than threefold compared to control in heat shock protein 16.2, heat shock protein 70, metallothionein 2, cytochrome P450 family protein 35A2, glutathione-S-transferase 4, superoxide dismutase 1, catalase 2, C. elegans p53-like protein 1, and apoptosis enhancer 1 genes. The lead-, chromium-, and arsenite-exposed nematode, on the other hand, showed little change in gene expression. Alterations in growth and reproduction were observed in cadmium- and chromium-exposed worms. To consider a transgenic nematode as a biosensor for toxicity monitoring, the responses of stress-related gene promoters need to be tested with a variety of metals. The overall results suggest that cadmium exhibits a high level of tolerance compared to the other metals tested. Use of the responses of stress-related gene expression therefore has considerable potential as a sensitive biomarker for the diagnosis of cadmium contamination, and C. elegans seems to be a good biological model for this approach.
 ...
PMID:Assessment of stress-related gene expression in the heavy metal-exposed nematode Caenorhabditis elegans: a potential biomarker for metal-induced toxicity monitoring and environmental risk assessment. 1708 18

Ascorbate (Asc) plays a key role in reductive activation of carcinogenic chromium(VI) in vivo. In addition to much higher rates (t(1/2) = 1 min for 1 mM Asc), its reactions at physiological conditions differ from other reducers by low yields of Cr(V) intermediates. Human cells in culture are severely Asc deficient, which results in distorted metabolism and potentially abnormal responses to Cr(VI). We found that restoration of physiological Asc levels in human lung cells (primary IMR90 fibroblasts and epithelial H460 cells) increased clonogenic lethality and apoptosis by Cr(VI). Enhanced cytotoxicity in mass cultures was more evident after normalization for lower Cr uptake caused by leakage of Asc into media. Asc did not change uptake-adjusted yields of Cr-DNA adducts and had no effect on cytotoxicity when delivered shortly after Cr(VI) exposure. Protein and Ser-15 phosphorylation levels of p53 did not show any association with the presence of Asc and there were no increases in p53-driven reporter activity in Cr-treated cells. Stable silencing of p53 expression by short hairpin RNA (shRNA) had no effect on toxicity of Cr(VI) in both -Asc and +Asc IMR90 and H460 cells. In contrast, shRNA-mediated depletion of essential components of MutS or MutL mismatch repair complexes greatly improved survival of all Cr-treated cells and eliminated Asc-potentiated effects on cell death. Thus, mismatch repair-mediated enhancement of Cr(VI) cytotoxicity by Asc should promote the selection of MSI+/wt-p53 phenotype found among chromate-induced human lung cancers. Our findings also indicate that Asc plays a dual role in Cr(VI) toxicity: protective outside and potentiating inside the cell.
 ...
PMID:Cellular vitamin C increases chromate toxicity via a death program requiring mismatch repair but not p53. 1730 Oct 63

The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) is a key component in cell cycle control and apoptosis, directing an anti-apoptotic response following DNA damage. Chromium exposure resulted in a 500-1000 fold increase in apoptosis-induced cell death in p21-/- HCT116 cells compared to wild-type or p53-/- cells. p53 shRNA (or transient p53 siRNA) into p21-/- HCT116 cells reduced Cr(VI) sensitivity, suggesting the enhanced apoptosis in p21-/- cells is p53-dependent. Under non-DNA damage conditions, the p53 level in p21-/- cells was significantly higher than in wild-type cells, due to enhanced p53 phosphorylation and stabilization rather than elevated p53 transcription. Wild-type cells showed significant p53 protein induction upon DNA damage whereas p21-/- cells showed no p53 increase. p21-/- cells display the constitutive activation of upstream p53 kinases (ATM, DNA-PK, ATR, AKT and p38). 2D gel analysis revealed p53 patterns in p21-/- cells were distinct from those in wild-type cells before and after chromium exposure. Our results suggest that p21 has an important role in the cellular response to normal replicative stress and its absence leads to a "chronic DNA damage" state that primes the cell for p53-dependent apoptosis.
 ...
PMID:Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p21-/- HCT116 colon cancer cells. 1802 14

Hexavalent chromium [Cr(VI)] is an ubiquitous environmental contaminant and a well-known etiological agent of human lung cancer. Inside human cells, Cr(VI) is reduced to Cr(III), which can conjugate with amino acids, ascorbic acids, and glutathiones in the cytoplasm. Conjugated and unconjugated Cr(III) can enter the nucleus to form adducts with DNA and electrostatically interact with the phosphate group of DNA. It has been found that in both human and Escherichia coli systems, Cr(III) ligand-conjugated DNA ternary adducts are efficiently repaired by the nucleotide excision repair (NER) pathway. In contrast, DNA adducts formed by unconjugated Cr(III) with DNA are repaired significantly less efficiently by the NER system. These results raise the possibility that the NER system repairs Cr(III) ligand-conjugated DNA adducts and biadducts such as Cr(III)-guanine-phosphate adducts but not Cr(III)-phosphate adducts. To test this hypothesis, we determined the cutting efficiency and the mode of cutting of DNA modified with tannin-conjugated Cr(III) by the E. coli NER enzymes UvrABC. Tannin compounds, gallic acid (GA), and ethyl gallate (EGA) can reduce Cr(VI) to Cr(III) to form Cr(III)-GA 2 and Cr(III)-EGA 2, respectively, which can interact with a single guanine or adenine base but not with the DNA phosphate backbone. We found that UvrABC is able to incise Cr(III)-GA 2- and Cr(III)-EGA 2-modified plasmid DNA, and the amount of incision increased as a function of tannin concentration used for modifications. In contrast, UvrABC nuclease does not incise GA- and EGA-modified plasmid DNA. Mapping the sequence specificity of Cr(III)-GA 2- and Cr(III)-EGA 2-DNA formation in the human p53 gene sequence by UvrABC nuclease cutting, we found that the sequence specificity for both adducts is the same but is much more selective than Cr(III)-guanine-DNA adducts. Together, these results suggest that NER proteins from E. coli recognize the purine-Cr(III) adduct but not the Cr(III)-backbone phosphate complex.
 ...
PMID:Recognition and incision of Cr(III) ligand-conjugated DNA adducts by the nucleotide excision repair proteins UvrABC: importance of the Cr(III)-purine moiety in the enzymatic reaction. 1845 13

Hexavalent chromium (Cr (VI)) is a highly toxic metal. Exposure to Cr (VI) compounds may affect reproductive functions. Due to the importance of anterior pituitary hormones on reproductive physiology we have studied the effects of Cr (VI) on anterior pituitary. We previously demonstrated that, after in vivo Cr (VI) administration, Cr accumulates in the pituitary gland and affects prolactin secretion. In vitro, Cr (VI) causes apoptosis in anterior pituitary cells due to oxidative stress generation. To better understand the mechanisms involved in Cr (VI)-induced apoptosis we studied: (a) whether Cr (VI) affects the intracellular antioxidant response and (b) which of the apoptotic factors participates in Cr (VI) effect. Our results show that Cr (VI) treatment induces a decrease in catalase and glutathione peroxidase (GPx) activity but does not modify glutathione reductase (GR) activity. Cr (VI) exposure causes an increase of GSH levels. p53 and Bax mRNA are also upregulated by the metal. Pifithrin alpha, a p53 transcriptional inhibitor, increases Cr (VI) cytotoxicity, suggesting a role of p53 as a survival molecule. The antioxidant N-acetyl-cysteine (NAC) could prevent Bax mRNA increase and caspase 3 activation, confirming that Cr (VI)-induced apoptosis involves oxidative stress generation.
 ...
PMID:Mechanisms of chromium (VI)-induced apoptosis in anterior pituitary cells. 1854 7

Chromium (Cr) has been widely used in industry for more than one century. Exposure to hexavalent Cr compounds is strongly associated with increasing risk of lung cancer. Extensive researches at DNA level indicated that generation of ROS from the reduction of Cr(VI) leading to DNA damage is the major cause of the toxicity and carcinogenicity of Cr(VI). The present study in cellular and protein levels confirmed that Cr(VI) induced apoptosis of lung epithelial cells (LEC) via ROS generation. To view the differentially expressed proteins in the process of Cr(VI) reduction, subcellular proteomics was applied and allowed the identification of more than 30 proteins with expression alteration. Most of those proteins are correlated with ROS-elicited responses, which were further validated by Western blotting analysis, induction of p53 pathway and antioxidative treatment. The current findings provided additional evidence in protein level to support the claim that ROS generated during the process of Cr(VI) reduction are involved in the Cr(VI)-induced toxicity and carcinogenesis.
 ...
PMID:Proteomic analysis of chromium cytotoxicity in cultured rat lung epithelial cells. 1856 48


<< Previous 1 2 3 4 5 6 7 8 Next >>