Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human epidermis with an area of 1.8 m(2) is the outer most layer of the human body. Hence, this organ plays a pivotal role in the defence against reactive oxygen species (ROS) generated by UV or X-ray exposure, heat and other sources. Consequently, a plethora of defence mechanisms exist controlling the redox status in this compartment. The role of thioredoxin reductase (TR), thioredoxin (T) in antioxidant defence has gained widespread recognition. In the past it has been shown that thioredoxin protects against UVB-induced skin injury, as well as against peroxidative damage. Under normal conditions, TR reduces oxidised thioredoxin in the presence of NADPH. Reduced thioredoxin serves as an electron donor for thioredoxin peroxidase (TPx) which consequently reduces H(2)O(2) to H(2)O. In this context, it has been demonstrated that membrane associated TR correlates with different skin photo types I-VI (Fitzpatrick classification), where darker skin has significantly higher enzyme activity compared to very fair skin, underlining the importance of this system in ROS defence. Moreover, it was only recently demonstrated in vivo with non-invasive Fourier-Transform Raman spectroscopy that UVB generates H(2)O(2) in the epidermis in a dose-dependent manner. H(2)O(2) can oxidise the selenocysteine residue in the penultimate position of the carboxyl terminus of TR with a K(m) of 2.5 mM. This oxidation is followed by an upregulation of mRNA expression of the enzyme. Hence, it can be concluded that UVB generated H(2)O(2) induces TR. However, permanent H(2)O(2) levels induce the tumour suppressor p53 which in turn downregulates cytosolic TR. Therefore TR activities are under fine control by H(2)O(2). This conclusion is also supported by the observation that thioredoxin, the substrate for TR, migrates from the cytosol to the nucleus after UVB exposure. A new function for the TR/T/TPx system in epidermal cells has been discovered in the control of the important cofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH(4)) homeostasis. Full oxidation of 6BH(4) to 6 biopterin via H(2)O(2) can lead to a cytotoxic environment for epidermal melanocytes. This cascade of events is observed in the depigmentation disorder vitiligo, where millimolar levels of H(2)O(2) can accumulate in the epidermis of affected individuals, consequently leading to cellular vacuolation in this compartment.
...
PMID:Thioredoxin reductase - its role in epidermal redox status. 1174 5

The interferon (IFN)-beta and all-trans-retinoic acid combination suppresses tumor growth by inducing apoptosis in several tumor cell lines. A genetic technique permitted the isolation of human thioredoxin reductase (TR) as a critical regulator of IFN/all-trans-retinoic acid-induced cell death. Our recent studies have shown that TR1:thioredoxin 1-regulated cell death is effected in part through the activation of p53-dependent responses. To understand its death regulatory function, we have performed a mutational analysis of TR. Human TR1 has three major structural domains, the FAD binding domain, the NADPH binding domain, and an interface domain (ID). Here, we show that the deletion of the C-terminal interface domain results in a constitutive activation of TR-dependent death responses and promotes p53-dependent gene expression. TR mutant without the ID still retains its dependence on thioredoxin for promoting these responses. Thus, our data suggest that TR-ID acts as a regulatory domain.
...
PMID:Mutational analysis of human thioredoxin reductase 1. Effects on p53-mediated gene expression and interferon and retinoic acid-induced cell death. 1195 36

Polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke may cause human lung cancer via metabolic activation to ultimate carcinogens. p53 is one of the most commonly mutated tumor suppressor genes in this disease. An analysis of the p53 mutational database shows that G to T transversions are a signature mutation of lung cancer. Aldo-keto reductases (AKRs) activate PAH trans-dihydrodiol proximate carcinogens to yield their corresponding reactive and redox-active o-quinones, e.g., benzo[a]pyrene-7,8-dione (BP-7,8-dione). We employed a yeast reporter system to determine whether PAH o-quinones or the ROS they generate cause change-in-function mutations in p53. N-Methyl-N-nitroso-N'-nitro-guanidine, a standard alkylating mutagen was used as a positive control. MNNG caused a dose-dependent increase in mutant yeast colonies and at the highest concentrations 8-14% of the yeast colonies were mutated and were characterized by G:C to A:T transitions in the p53 DNA binding domain. Treatment of p53 cDNA with micromolar concentrations of (+/-)-anti-7,8-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene, (anti-BPDE, an ultimate carcinogen) or sub-micromolar concentrations of BP-7,8-dione in the presence of redox-cycling conditions (NADPH and CuCl(2)) also caused p53 mutations in a dose-dependent manner. We found that no mutants were observed with PAH o-quinones or NADPH alone. p53 mutagenesis by BP-7,8-dione was attenuated by ROS scavengers and completely abrogated by a combination of superoxide dismutase and catalase, indicating that both superoxide anion and hydroxyl radicals were the responsible mutagens. The bulk of the mutations detected were single-point mutations and were not random in occurrence. Over 46% of BP-7,8-dione-induced mutations were G:C to T:A transversions, consistent with the formation of 8-oxo-dGuo or its secondary oxidation products. In addition, 25% of these mutations were at hotspots in p53 which are known to be mutated in lung cancer. Together these data suggest that PAH o-quinones generate an endogenous mutagen (ROS) which leads to p53 inactivation. These observations provide an alternative route to G to T transversions that dominate in p53 in lung cancer.
...
PMID:Reactive oxygen species generated by PAH o-quinones cause change-in-function mutations in p53. 1206 51

The p53 tumor suppressor protein, a transcription factor, induces cell cycle arrest and apoptosis via the upregulation of downstream target genes. Ferredoxin Reductase (protein, FR; gene, FDXR) transfers electron from NADPH to cytochrome P450 via ferredoxin in mitochondria. Here, we identified FDXR as a target gene of the p53 family, that is, p53, p63, and p73. We found that FDXR can be induced by DNA damage in cells in a p53-dependent manner and by a mutated form of p53 that is competent in inducing apoptosis. In addition, we identified a p53 response element located within the FDXR promoter that is responsive to wild-type p53, p63alpha, p63gamma, p73alpha, and p73beta. Furthermore, we showed that p53, p63alpha and p73alpha directly bind to the p53 response element in vivo and promote the accessibility of the FDXR promoter by increasing the acetylation of histones H3 and H4. To determine the role of FR in p53 tumor suppression, we generated cell lines that express FR using a tetracycline-regulated promoter. We found that over-expression of FR in lung H1299, breast MCF7, and colorectal HCT116 carcinoma cells have no effect on cell proliferation. However, we showed that FR increases the sensibility of H1299 and HCT116 cells to 5-fluorouracil-, doxorubicin- and H(2)O(2)- mediated apoptosis. Our data support a model of feed-forward loop for p53 activity, that is, various cellular stresses, including reactive oxygen species (ROS), activate p53, which induces the expression of FDXR; and the FDXR gene product, FR, in turn sensitizes cells to ROS-mediated apoptosis.
...
PMID:The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. 1237 Aug 9

The cytotoxic effects of menadione and hydrogen peroxide were examined in two hepatic stellate cell lines derived from normal or cirrhotic rat liver. The cirrhotic fat-storing cells (CFSC) were found more resistant than the normal fat-storing cells (NFSC) to menadione cytotoxicity. No significant differences were observed in hydrogen peroxide toxicity in these two cell lines. Although protein levels and enzymatic activities of catalase, Cu,Zn-SOD, Mn-SOD, and NADPH cytochrome c reductase were similar in these cell lines, 20-fold increases of NAD(P)H:quinone oxidoreductase 1 (NQO1) enzymatic activity and protein levels were detected in CFSC compared to those of NFSC. Gel mobility shift assays and functional analysis using transient transfection experiments indicated the involvement of the electrophile responsive element (EPRE) in the up-regulation of the NQO1 expression. Antibody supershift analysis revealed that, although Nrf2 is a member of the EPRE-binding complex in both NFSC and CFSC, Nrf1 was identified as a part of the protein/DNA complex only in CFSC. Expression of p53 tumor suppressor gene was found in higher levels in CFSC than in NFSC. We conclude that activation of the EPRE-signaling pathway, which up-regulates several phase II genes and affects p53 stabilization, may offer resistance to hepatic stellate cells against oxidative damage during hepatic injury. This resistance may be a part of the activation process of the hepatic stellate cells and could contribute to their increased proliferation and production of extracellular matrix.
...
PMID:Involvement of the electrophile responsive element and p53 in the activation of hepatic stellate cells as a response to electrophile menadione. 1272 13

Exposure to the environmental contaminant dioxin, elicits a variety of responses, which includes tumor promotion, embryotoxicity/teratogenesis, and carcinogenesis in both animals and humans. Many of the effects of dioxin are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated bHLH (basic helix-loop-helix)/PAS transcription factor. We initiated this study to determine whether dioxin's tumor-promoting activities may lie in its ability to alter proliferation, differentiation, and/or senescence using normal human epidermal keratinocytes (HEKs). Here, we report that dioxin appears to accelerate differentiation as measured by flow cytometry and by increased expression of the differentiation markers involucrin and filaggrin. In addition, dioxin appears to increase proliferation as indicated by an increase in NADH/NADPH production and changes in cell cycle. Finally, dioxin decreases SA (senescence associated) beta-galactosidase staining, an indicator of senescence, in the differentiating keratinocytes. These changes were accompanied by decreases in the expression levels of key cell cycle regulatory proteins p53, p16INK4a, and p14ARF. Our findings support the idea that dioxin may exert its tumor-promoting actions, in part, by downregulating the expression levels of key tumor suppressor proteins, which may impair the cell's ability to maintain its appropriate cellular status.
...
PMID:Alteration of keratinocyte differentiation and senescence by the tumor promoter dioxin. 1455 Jul 47

The selenoprotein thioredoxin reductase (TrxR1) is an integral part of the thioredoxin system. It serves to transfer electrons from NADPH to thioredoxin leading to its reduction. Interestingly, recent work has indicated that thioredoxin reductase can regulate the activity of transcription factors such as p53, hypoxia-inducible factor, and AP-1. Here, we describe that an alternative splicing variant of thioredoxin reductase (TrxR1b) containing an LXXLL peptide motif, is implicated in direct binding to nuclear receptors. In vitro interaction studies revealed direct interaction of the TrxR1b with the estrogen receptors alpha and beta. Confocal microscopy analysis showed nuclear colocalization of the TrxR1b with both estrogen receptor alpha and beta in estradiol-17beta-treated cells. Transcriptional studies demonstrated that TrxR1b can affect estrogen-dependent gene activation differentially at classical estrogen response elements as compared with AP-1 response elements. Based on these results, we propose a model where thioredoxin reductase directly influences the estrogen receptor-coactivator complex assembly on non-classical estrogen response elements such as AP-1. In summary, our results suggest that TrxR1b is an important modulator of estrogen signaling.
...
PMID:An alternative splicing variant of the selenoprotein thioredoxin reductase is a modulator of estrogen signaling. 1519 63

Ionizing radiation induces the production of reactive oxygen species, which play an important causative role in apoptotic cell death. Therefore, compounds that scavenge reactive oxygen species may confer regulatory effects on apoptosis. Superoxide dismutase (SOD) mimetics have been shown to be protective against cell injury caused by reactive oxygen species. We investigated the effects of the manganese (III) tetrakis(N-methyl-2-pyridyl)porphyrin (MnTMPyP), a cell-permeable SOD mimetic, on ionizing radiation-induced apoptosis. Upon exposure to 2 Gy of gamma-irradiation, there was a distinct difference between the control cells and the cells pre-treated with 5 microM MnTMPyP for 2 h with regard to apoptotic parameters, cellular redox status, mitochondria function, and oxidative damage to cells. MnTMPyP effectively suppressed morphological evidence of apoptosis and DNA fragmentation in U937 cells exposed to ionizing radiation. The [GSSG]/[GSH+GSSG] ratio and the generation of intracellular reactive oxygen species were higher and the [NADPH]/[NADP(+)+NADPH] ratio was lower in control cells compared to MnTMPyP-treated cells. The ionizing radiation-induced mitochondrial damage reflected by the altered mitochondrial permeability transition, the increase in the accumulation of reactive oxygen species, and the reduction of ATP production were significantly higher in control cells compared to MnTMPyP-treated cells. MnTMPyP pre-treated cells showed significant inhibition of apoptotic features such as activation of caspase-3, up-regulation of Bax and p53, and down-regulation of Bcl-2 compared to control cells upon exposure to ionizing radiation. This study indicates that MnTMPyP may play an important role in regulating the apoptosis induced by ionizing radiation presumably through scavenging of reactive oxygen species.
...
PMID:Regulation of ionizing radiation-induced apoptosis by a manganese porphyrin complex. 1600 45

Thioredoxin reductase 1 (TrxR1) is a cytosolic enzyme that plays a central role in controlling cellular redox homeostasis. TrxR1 can transduce regulatory redox signals through NADPH-dependent reduction of thioredoxin (Trx), which is able to reduce a broad spectrum of target enzymes and regulate the activity of several transcription factors (e.g., p53 and NF-kappaB). The TrxR1/Trx system is involved in every step of cancer biology, ranging from transformation and progression to invasion, metastasis and resistance to therapy. TrxR1 was also recently identified as one key enzyme involved in cell death induced by interferon-beta (IFN-beta)/all-trans retinoic acid (ATRA) anti-cancer treatment. Our study employed small interference RNA (siRNA) and microarray techniques to investigate the effect of TrxR1 silencing on gene expression in HepG2 cells. We also investigated TrxR1-mediated cell response to IFN-beta/ATRA treatment. We identified TrxR1-dependent genes with functions related to several cellular processes such as apoptosis (SOX4), ubiquitination (Ubiquitin D, F-box protein 25), organization of cytoskeletal/extracellular matrix (Keratin 19, Fibronectin 1) and transport (Cystine/Glutamate transporter). We also investigated the effect of TrxR1 siRNA on the protein profile using surface enhanced laser desorption ionization time-of-flight (SELDI-TOF) technology. Profiles confirmed significant involvement of TrxR1 in cell response to IFN-beta/ATRA.
...
PMID:Identification of thioredoxin reductase 1-regulated genes using small interference RNA and cDNA microarray. 1609 67

Apoptosis is a major mechanism of cancer cell destruction by chemotherapy and radiotherapy. The anthracycline class of antitumor drugs undergoes redox cycling in living cells producing increased amounts of reactive oxygen species and semiquinone radical, both of which can cause DNA damage, and consequently trigger apoptotic death of cancer cells. We show here that MCF-7 cells overexpressing thioredoxin (Trx) were more apoptotic in response to daunomycin. Trx overexpression in MCF-7 cells increased the generation of superoxide anion (O2*-) in anthracycline-treated cell extracts. Enhanced generation of O2- in response to daunomycin inTrx-overexpressing MCF-7 cells was inhibited by diphenyleneiodonium chloride, a general NADPH reductase inhibitor, demonstrating that Trx provides reducing equivalents to a bioreductive enzyme for redox cycling of daunomycin. Additionally Trx increased p53-DNA binding and expression in response to anthracyclines. MCF-7 cells expressing mutant redox-inactive Trx showed decreased superoxide generation, apoptosis, and p53 protein and DNA binding. In addition, down-regulation of endogenous Trx expression by small interfering RNA resulted in decreased expression of caspase-7 and cleaved poly(ADP-ribose) polymerase expression in response to daunomycin. These results suggest that endogenous Trx is required for anthracycline-mediated apoptosis of breast cancer cells. Taken together, our data demonstrate a novel pro-oxidant and proapoptotic role of Trx in anthracycline-mediated apoptosis in anthracycline chemotherapy.
...
PMID:Endogenous thioredoxin is required for redox cycling of anthracyclines and p53-dependent apoptosis in cancer cells. 1615 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---