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)

Multidrug resistance (MDR) is associated with the overproduction of the 170-kDa transmembrane protein P-glycoprotein (MDR1) caused by transcriptional activation. However, the activity of the MDR1 promoter in response to different doses of ionizing radiation has not been investigated. In this study, two squamous cell carcinoma oral cavity cell lines, T-167 and T-409, were exposed to either a standard clinical dose of 2 Gy or low-dose fractionated radiation therapy (LDFRT), delivered as 0.5 Gy in four fractions. MDR1 gene expression and degree of cell death were assessed. Clinically relevant 2-Gy dose of radiation resulted in increased expression of MDR1 by reverse transcription-PCR and luciferase reporter assays in both cell lines (T-167 and T-409), whereas LDFRT did not. LDFRT caused enhanced apoptosis when compared with the 2-Gy dose in T-167 and T-409 cells as assessed by terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) assays. Transcription of the MDR1 gene is regulated by numerous transcription factors, which include nuclear factor-kappaB (NF-kappaB), NF-Y, SP1, YB1, MEF1 (MDR1 promoter-enhancing factor 1), p53, and NF-R1. Interestingly, 2 Gy robustly induced both NF-kappaB and NF-Y in T-167 and T-409 cells, but did not show induction when exposed to LDFRT. Silencing the expression of the DNA binding subunit of NF-kappaB, p50, by small interfering RNA vector resulted in a decrease of MDR1 function by rhodamine 123 efflux assay in T167 cells exposed to 2 Gy. Together, these results provide evidence for the lack of induction of P-glycoprotein expression by LDFRT, which has important implications in combinatorial cancer therapy, including the use of LDFRT as an adjuvant for chemotherapy.
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PMID:Lack of P-glycoprotein expression by low-dose fractionated radiation results from loss of nuclear factor-kappaB and NF-Y activation in oral carcinoma cells. 1823 65

Cancer-cell resistance to chemotherapy limits the efficacy of cancer treatment. The primary mechanisms of multidrug resistance (MDR) are "pump" and "non-pump" resistance. We evaluated the effects and mechanisms of glycocholic acid (GC), a bile acid, on inhibiting pump and non-pump resistance, and increasing the chemosensitivity of epirubicin in human colon adenocarcinoma Caco-2 cells and rat intestine. GC increased the cytotoxicity of epirubicin, significantly increased the intracellular accumulation of epirubicin in Caco-2 cells and the absorption of epirubicin in rat small intestine, and intensified epirubicin-induced apoptosis. GC and epirubicin significantly reduced mRNA expression levels of human intestinal MDR1, MDR-associated protein (MRP)1, and MRP2; downregulated the MDR1 promoter region; suppressed the mRNA expression of Bcl-2; induced the mRNA expression of Bax; and significantly increased the Bax-to-Bcl-2 ratio and the mRNA levels of p53, caspase-9 and -3. This suggests that GC- and epirubicin-induced apoptosis was mediated through the mitochondrial pathway. We conclude that simultaneous suppression of pump and non-pump resistance dramatically increased the chemosensitivity of epirubicin. A combination of anticancer drugs with GC can control MDR via a mechanism that involves modulating P-gp and MRPs as well as regulating apoptosis-related pathways.
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PMID:Inhibit multidrug resistance and induce apoptosis by using glycocholic acid and epirubicin. 1860 22

To investigate the relationship between the expression of early growth response gene 1 (EGR-1) and p38MAPK pathway in the paclitaxel resistance of ovarian carcinoma cells, the effect of p38MAPK inhibitor SB203580 on cell apoptosis was examined by using Hoechst 33258 staining. The intracellular Rh123 (Rhodamine 123) accumulation was detected by the flow cytometry (FCM). The 50% inhibition concentration (IC50) of paclitaxel for A2780/Taxol cells was determined by MTT method. Electrophoretic motility shift assay (EMSA) was employed to examine the EGR-1DNA binding activity. MDR1 and EGR-1 mRNA were assessed by RT-PCR. The expressed of p-gp, phosphorylated p53 and p38 were detected by Western blotting. SB203580 could remarkably promote the apoptosis of A2780/Taxol cells, and the cell apoptosis was in a time-dependent manner. Cellular Rh123 accumulation was increased, and the IC50 of paclitaxel for A2780/Taxol cells was decreased significantly. A2780/Taxol cell line after SB203580 treatment was shown to have a significantly higher level of EGR-1 DNA binding activity. SB203580 down-regulated the activity of p38MAPK pathway, but up-regulated EGR-1 expression. SB203580 significantly increased the level of cellular phosphorylated p53 protein, but decreased the p-gp protein level and MDR1 mRNA level in A2780/Taxol cells. There existed a close relationship between p38MAPK pathway and the paclitaxel resistance of ovarian carcinoma cells. The expression of EGR-1 mediated by p38MAPK pathway plays a critical role in paclitaxel resistance of ovarian carcinoma cells.
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PMID:Targeting of p38 mitogen-activated protein kinases to early growth response gene 1 (EGR-1) in the human paclitaxel-resistance ovarian carcinoma cells. 1870 10

Human mutant-type (mt) p53 cDNA was synthesized and cloned from human lung cancer cell line GL containing mt-p53 gene by using polymerase chain reaction (PCR). It was confirmed that the mt-p53 cDNA contained the complete coding sequence of p53 gene but mutated at codon 245 (G-->T) and resulted in glycine to cysteine by sequencing analysis. The retroviral vector pD53M of the mt-p53 was constructed and introduced into the drug-sensitive human lung cancer cells GAO in which p53 gene did not mutate. The transfected GAO cells strongly expressed mutant-type p53 protein by immunohistochemistry, showing that pD53M vector could steadily express in GAO cells. The drug resistance to several anticancer agents of GAO cells infected by pD53M increased in varying degrees, with the highest increase of 4-fold,in vitro andin vivo. By quantitative PCR and flow cytometry (FCM) analyses, the expression of MDR1 gene and the activity of P-glycoprotein (Pgp) did not increase, the expression of MRP gene and the activity of multidrug resistance-related protein (Mrp) increased slightly. These results indicated that the drug resistance associated with mt-p53 gene might be somewhat correlated with MRP/Mrp but not with MDR1/Pgp. It was possible to modify the tumor drug resistance by changing status of p53 gene.
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PMID:Increasing drug resistance in human lung cancer cells by mutant-type p53 gene mediated by retrovirus. 1872 4

During the annual cycle, oysters are exposed to seasonal slow changes in temperature, but during emersion at low tide on sunny summer days, their internal temperature may rise rapidly, resulting in acute heat stress. We experimentally exposed oysters to a 1-h acute thermal stress and investigated the transcriptional expression level of some genes involved in cell stress defence mechanisms, including chaperone proteins (heat shock proteins Hsp70, Hsp72 and Hsp90 (HSP)), regulation of oxidative stress (Cu-Zn superoxide dismutase, metallothionein (MT)), cell detoxification (glutathione S-transferase sigma, cytochrome P450 and multidrug resistance (MDR1)) and regulation of the cell cycle (p53). Gene mRNA levels were quantified by reverse transcription-quantitative polymerase chain reaction and expressed as their ratio to actin mRNA, used as a reference. Of the nine genes studied, HSP, MT and MDR1 mRNA levels increased in response to thermal stress. We compared the responses of oysters exposed to acute heat shock in summer and winter and observed differences in terms of magnitude and kinetics. A larger increase was observed in September, with recovery within 48 h, whereas in March, the increase was smaller and lasted more than 2 days. The results were also compared with data obtained from the natural environment. Though the functional molecule is the protein and information at the mRNA level only has limitations, the potential use of mRNAs coding for cell stress defence proteins as early sensitive biomarkers is discussed.
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PMID:Transcriptional expression levels of cell stress marker genes in the Pacific oyster Crassostrea gigas exposed to acute thermal stress. 1900 5

Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC(50)s <3 micromol/L) than in p53-mutated cell lines (IC(50)s >17 micromol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)-overexpressing cell lines (decrease in IC(50)s 92- to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1-mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp-mediated drug efflux. In conclusion, nutlin-3-induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report.
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PMID:Reversal of P-glycoprotein-mediated multidrug resistance by the murine double minute 2 antagonist nutlin-3. 1914 53

Mutant p53 gain of function contributes to cancer progression, increased invasion and metastasis potentials, and resistance to anticancer therapy. The ability of mutant p53 to acquire its gain of function is shown to correlate with increased expression of progrowth genes, such as c-MYC, MDR1, and NF-kappaB2. However, most of the published studies to identify mutant p53 target genes were performed in a cell system that artificially overexpresses mutant p53. Thus, it remains unclear whether such mutant p53 targets can be regulated by endogenous physiological levels of mutant p53. Here, we utilized SW480 and MIA-PaCa-2 cells, in which endogenous mutant p53 can be inducibly knocked down, to identify mutant p53 target genes that potentially mediate mutant p53 gain of function. We found that knockdown of mutant p53 inhibits GRO1 expression, whereas ectopic expression of mutant R175H in p53-null HCT116 cells increases GRO1 expression. In addition, we found that endogenous mutant p53 is capable of binding to and activating the GRO1 promoter. Interestingly, ectopic expression of GRO1 can rescue the proliferative defect in SW480 and MIA-PaCa-2 cells induced by knockdown of mutant p53. Conversely, knockdown of endogenous GRO1 inhibits cell proliferation and thus abrogates mutant p53 gain of function in SW480 cells. Taken together, our findings define a novel mechanism by which mutant p53 acquires its gain of function via transactivating the GRO1 gene in cancer cells. Thus, targeting GRO1 for cancer therapy would be applicable to a large portion of human tumors with mutant p53, but the exploration of GRO1 as a potential target should take the mutation status of p53 into consideration.
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PMID:Identification of GRO1 as a critical determinant for mutant p53 gain of function. 1925 12

We report on the results of multidrug-resistance transporters (P-glycoprotein, LRP, and MDR1), and apoptosis-related proteins (Fas, Bcl-2, Bax, p53, and Bcl-X(L)) expression analysis of 56 acute myeloid leukemia (AML) patients by flow cytometry. Of these, there were 21 persons exposed to ionizing radiation due to the Chornobyl accident with radiation-associated and 35 patients with spontaneous AML. Leukemic cells in patients with radiation-associated AML more often overexpressed antiapoptotic protein Bcl-2 (12/21 vs. 6/35, p < 0.005) and less often demonstrated expression of Fas receptor (12/21 vs. 30/35, p < 0.05). Moreover, leukemic cells were simultaneously Fas negative and Bcl-2 positive in 4 out of 21 patients exposed to ionizing radiation but none of spontaneous cases had similar phenotype (p < 0.05). Patients with radiation-associated AML compared to spontaneous cases more often were P-glycoprotein positive (12/20 vs. 9/31, p < 0.05). P-glycoprotein overexpression significantly correlated with the resistance of the disease to chemotherapy in patients with radiation-associated AML (p < 0.05).
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PMID:Membrane transport and apoptosis-related proteins in radiation-associated acute myeloid leukemia following the Chornobyl accident. 1939 Jan 38

This study was designed to investigate the molecular changes that may develop during exposure of breast cancer cells to anticancer agents and that may lead to acquired resistance. We used two breast cancer cell lines, a parental (MCF7/WT) and a doxorubicin-resistant (MCF7/DOX) one. Cell survival, cell cycle distribution and RT-PCR expression level of genes involved in DNA damage response, MDR1, GST and TOPOIIalpha were measured. MCF7/DOX cells were five-fold more resistant to doxorubicin (DOX) than the MCF7/WT cells. DOX treatment causes arrest of MCF7/DOX cells in G1 and G2 phases of cell cycle whereas MCF7/WT cells were arrested in S-phase. The molecular changes in both cell lines due to DOX treatment could be classified into: (1) the basal level of p53, p21, BRCA1, GST and TOPOIIalpha mRNA was higher in MCF7/DOX than MCF7/WT. During DOX treatment, the expression level of these genes decreased in both cell lines but the rate of down-regulation was faster in MCF7/WT than MCF7/DOX cells. (2) The expression level of MDR1 was the same in both cell lines but 48 and 72 h of drug treatment, MDR1 disappeared in MCF7/WT but still expressed in MCF7/DOX. (3) There was no change in the expression level of BAX, FAS and BRCA2 in both cell lines. Conclusively, after validation in clinical samples, overexpression of genes like BRCA1, p53, p21, GST, MDR1 and TOPOIIalpha could be used as a prognostic biomarker for detection of acquired resistance in breast cancer and as therapeutic targets for the improvement of breast cancer treatment strategies.
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PMID:Altered expression of proliferation-inducing and proliferation-inhibiting genes might contribute to acquired doxorubicin resistance in breast cancer cells. 1959 73

Menopausal hormone therapy (HT) is associated with an increased breast cancer risk among postmenopausal women. In this study, we investigated genetic effect modification of HT associated breast cancer risk in 3,149 postmenopausal breast cancer patients and 5,489 controls from the two German population-based case-control studies MARIE and GENICA. Twenty-eight polymorphisms of 14 candidate genes including two drug and hormone transporter genes (ABCB1/MDR1 and SHBG), four genes involved in cell cycle regulation (BRCA1, P21/CDKN1A, STK15/AURKA and TP53), six cytokine genes (IGFBP3, IL6, TGFB1, TNF, LTA and IGF1), and two cytokine receptor genes (EGFR and ERBB2) were genotyped using validated methods. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and estrogen monotherapy use with regard to breast cancer risk assuming log-additive and co-dominant modes of inheritance. Women homozygous for the major ABCB1_rs2214102_G allele were found to be at a significantly increased breast cancer risk associated with combined estrogen-progestagen therapy [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.12-1.23, P (interaction) = 0.022]. Additionally, risk associated with estrogen monotherapy was modified by BRCA1_rs799917. We observed a trend with increasing minor T alleles leading to the highest risk in homozygous carriers of the minor allele [OR (95% CI) = 1.17 (0.98-1.39), 1.06 (0.98-1.14), and 1.02 (0.94-1.11) for homozygous minor, heterozygous, and homozygous major allele carriers, respectively; P (interaction) = 0.032]. Our results suggest that genetic variants in ABCB1 and BRCA1 may modify the effect of HT on postmenopausal breast cancer risk.
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PMID:Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. 1967 6


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