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)

It is not completely understood how certain epithelial cells harboring mutant p53 have better response to chemotherapy. We investigate the mechanism of cisplatin-induced apoptosis in two resistant cell lines (parental TCCSUP and R273L mutant p53 transfectant) and two sensitive cell lines (V143A and N247I mutant p53 transfectants). Activation of caspase 9 was demonstrated by Western blotting, and specific inhibitor for caspase 9 could inhibit apoptosis. Inhibitors for caspases 1, 2, 6, and 8 had no effect on apoptosis. Transcriptional repression of Bcl-2 occurred during apoptosis and could be reversed by the treatment of histone deacetylase inhibitor trichostatin A (TSA). The expression of Noxa, p53 inducible ribonucleotide reductase subunit 2 (p53R2), and p53 inducible death domain (PIDD) gene were not elevated with treatment of cisplatin (CDDP). Surface trafficking of Fas or Fas-L was not observed. Ser15 of wild-type p53 and mutant p53 was phosphorylated in response to cisplatin. Acetylation of wild-type p53 increased, while acetylation of mutant p53 decreased during cisplatin treatment. Both transcriptional inhibitor actinomycin D and translational inhibitor cycloheximide did not inhibit apoptosis. These results indicated that phosphorylated and hypoacetylated mutant p53 could enhance cisplatin-induced apoptosis through activation of caspase 9 independent of transcriptional activation and translation.
 ...
PMID:Phosphorylated and hypoacetylated mutant p53 enhances cisplatin-induced apoptosis through caspase-9 pathway in the absence of transcriptional activation or translation. 1575 39

A mouse leukemia L1210 cell line (Y8), selected for resistance to deoxyadenosine, has a markedly altered phenotypic expression that includes loss of sensitivity to dATP as an allosteric inhibitor of ribonucleotide reductase, increased expression of c-myc, c-fos and WAF1/p21, but decreased expression of p53. In addition, the Y8 cells have a Very strong apoptotic response to a variety of agents under conditions in which the parental wild-type cells do not apoptose. In these studies, we show that flavopiridol (a cdk inhibitor) causes the Y8 cells to undergo apoptosis via a caspase-3 activation process. The apoptotic response to flavopiridol is markedly enhanced by LY294002. Data also show that the apoptotic response of the Y8 cells to roscovitine (a cdk inhibitor) is enhanced by UCN-01 (a PKC inhibitor). These data show that simultaneous blockage of specific pathways leads to increased apoptosis in the Y8 cells with essentially no effects on the parental wild-type L1210 cells.
 ...
PMID:Blockage of cyclin cdk's, PKC and phosphoinositol 3-kinase pathways leads to augmentation of apoptosis in drug-resistant leukemia cells: evidence for interactive effects of flavopiridol, LY 294002, roscovitine,wortmannin and UCN-01. 1581 25

In addition to their well-known anti-malarial activity, artemisinin and its derivatives (1,2,4-trioxanes) possess potent activity against tumor cells in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. These genes are from classes with different biological function; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Anti-oxidant stress genes (thioredoxin, catalase, gamma-glutamyl-cysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines over-expressing genes that confer resistance to established anti-tumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that this drug has a different target and is not subject to multidrug resistance. The Plasmodium translationally controlled tumor protein (TCTP) represents a known target protein of artemisinin and its derivatives in the malaria parasite. The microarray-based mRNA expression of human TCTP correlated with sensitivity to artesunate in tumor cells, suggesting that human TCTP contributes to response of tumor cells to the drug. The multi-factorial nature of cellular response to artemisinin and its derivatives may be beneficial to treat otherwise drug-resistant tumors and may explain why resistance development has not been observed in either cancer or malaria.
 ...
PMID:Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. 1587 3

The p53R2 gene encodes the ribonucleotide reductase (RR) small subunit 2 homologue, and is induced by several stress signals activating p53, such as DNA-damaging agents. The p53R2 gene product causes an increase in the deoxynucleotide triphosphate (dNTP) pool in the nucleus, which facilitates DNA repair and synthesis. We hypothesized that p53R2 would be a good molecular target for cancer gene therapy. In this study, three human oral cancer cell lines (SAS, HSC-4 and Ca9-22), a human breast cancer cell line MCF-7, and a normal human fibroblast cell line NHDF were tested. We silenced the expression of p53R2 with the highly specific post-transcriptional suppression of RNA interference (RNAi). We investigated p53R2 expression with the reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The sensitivity to anticancer agents was evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of p53R2 showed no association with the mutational status of p53. The cancer cell lines with higher p53R2 expression were more resistant to 5-FU. RNAi-mediated p53R2 reduction selectivity inhibited growth and enhanced chemosensitivity in cancer cell lines but not in normal fibroblasts. These results suggest that basal transcription of p53R2 could be associated with the sensitivity to anticancer agents. Moreover, we assessed the possibility that p53R2 would be a good molecular target, and report that RNAi targeting of p53R2 could be useful for oral cancer gene therapy.
 ...
PMID:Silencing of the p53R2 gene by RNA interference inhibits growth and enhances 5-fluorouracil sensitivity of oral cancer cells. 1589 Feb 38

With ulcerative colitis (UC)-associated tumorigenesis, p53 gene alteration is considered to be a key event. To clarify whether the p53-checkpoint is operating in foci of inflammation and that its disruption is a feature of UC-associated neoplasms, the present immunohistochemical study was conducted. Since accumulation of butyric acid with active UC is associated with apoptosis, effects of in vitro exposure of newly established UC-cancer derived cell lines to organic acids were also assessed. The regulatory subunit of ribonucleotide reductase, p53R2, was found to be localized with p53 in situ, and levels of p53, phospho-p53, p53R2 and inducible nitric oxide synthase were significantly intercorrelated. However, p53R2 expression was clearly reduced with progression through UC-associated dysplasia to carcinoma, demonstrating an inverse relation with p53 overexpression. In vitro treatment with butyrate or propionic acid, but not succinic acid, elicited a positive response in the p53-p53R2 system. Moreover, p53-dependent DNA repair, investigated by radioactive nucleotide incorporation, was induced by butyric acid and inhibited by short-interfering p53 and p53R2 RNAs. Therefore, it was concluded that the p53-p53R2-dependent DNA repair system is constitutively stimulated by butyric acid, which accumulates in UC inflammatory lesions. Since failure of the p53-G(1) checkpoint may cause dysfunction of repair under the influence of butyrate, gene alterations may increase and spread through the genome, leading to tumorigenesis.
 ...
PMID:Disruption of the p53-p53r2 DNA repair system in ulcerative colitis contributes to colon tumorigenesis. 1620 88

p53R2, which encodes a subunit of ribonucleotide reductase, is activated by DNA damage induced by gamma-ray and ultraviolet irradiation, and also by genotoxic chemicals such as adriamycin. For the purpose of constructing an easy-operating genotoxicity test system using human cell lines, we developed a p53R2-dependent luciferase reporter gene assay, and demonstrated dose-dependent luminescence caused by adriamycin in two human cell lines that express wild-type p53, MCF-7 and HepG2. The performance of this assay system was evaluated with 80 chemicals including those known in the Ames test as genotoxic or non-genotoxic. When the luciferase activity of cells treated with the test sample was over 200% to that of control cells in a dose-dependent increasing manner, the sample was judged positive as a genotoxic chemical. Forty of 43 Ames-positive chemicals induced luciferase activity in this assay system. Eight Ames-negative chemicals also induced luciferase activity. These eight chemicals are genotoxic in other in vitro test systems using mammalian cells. It is suggested that this assay system can be applied to rapid screening of chemicals for potential human genotoxicity.
 ...
PMID:Genotoxicity test system based on p53R2 gene expression in human cells: examination with 80 chemicals. 1623 44

The p53 protein has been implicated in multiple cellular responses related to DNA damage. Alterations in any of these cellular responses could be related to increased genomic instability. Our previous study has shown that mutations in p53 lead to hypermutability to ionizing radiation. To investigate further how p53 is involved in regulating mutational processes, we used 8K cDNA microarrays to compare the patterns of gene expression among three closely related human cell lines with different p53 status including TK6 (wild-type p53), NH32 (p53-null), and WTK1 (mutant p53). Total RNA samples were collected at 1, 3, 6, 9, and 24 h after 10 Gy gamma-irradiation. Template-based clustering analysis of the gene expression over the time course showed that 464 genes are either up or downregulated by at least twofold following radiation treatment. In addition, cluster analyses of gene expression profiles among these three cell lines revealed distinct patterns. In TK6, 165 genes were upregulated, while 36 genes were downregulated. In contrast, in WTK1 75 genes were upregulated and 12 genes were downregulated. In NH32, only 54 genes were upregulated. Furthermore, we found several genes associated with DNA repair namely p53R2, DDB2, XPC, PCNA, BTG2, and MSH2 that were highly induced in TK6 compared to WTK1 and NH32. p53R2, which is regulated by the tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in radiation-induced mutagenesis, p53R2 protein was inhibited by siRNA in TK6 cells and followed by 2 Gy radiation. The background mutation frequencies at the TK locus of siRNA-transfected TK6 cells were about three times higher than those seen in TK6 cells. The mutation frequencies of siRNA-transfected TK6 cells after 2 Gy radiation were significantly higher than the irradiated TK6 cells without p53R2 knock down. These results indicate that p53R2 was induced by p53 protein and is involved in protecting against radiation-induced mutagenesis.
 ...
PMID:Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells. 1624 78

Hydroxyurea (HU) is a competitive inhibitor of ribonucleotide reductase that is used for the treatment of myeloproliferative disorders. HU inhibits DNA replication and induces apoptosis in a cell type-dependent manner, yet the relevant pathways that mediate apoptosis in response to this agent are not well characterized. In this study, we employed the human myeloid leukemia 1 (ML-1) cell line as a model to investigate the mechanisms of HU-induced apoptosis. Exposure of ML-1 cells to HU caused rapid cell death that was accompanied by hallmark features of apoptosis, including membrane blebbing, phosphatidylserine translocation, and caspase activation. HU-induced apoptosis required new protein synthesis, was induced by HU exposures as short as 15 min, and correlated with the accumulation of p53 and induction of the p53 target gene PUMA. p53 induction in ML-1 cells was ATR dependent and downregulation of p53 through RNAi delayed HU-induced apoptosis. HU did not induce p53 or induce apoptosis in Molt-3 leukemia cells, even though exposure to HU induced a comparable level of DNA damage and robustly activated the ATR pathway. The microtubule inhibitor nocodazole suppressed HU-induced p53 accumulation in ML-1 cells suggesting that a microtubule-dependent event contributes to p53 induction and apoptosis in this cell line. Our findings outline an HU-induced cell death pathway and suggest that activation of ATR is necessary, but not sufficient, for stabilization of p53 in response to DNA replication stress.
 ...
PMID:ATR activation necessary but not sufficient for p53 induction and apoptosis in hydroxyurea-hypersensitive myeloid leukemia cells. 1625 78

p53R2 is a newly identified small subunit of ribonucleotide reductase (RR) and plays a key role in supplying precursors for DNA repair in a p53-dependent manner. Currently, we are studying the redox property, structure, and function of p53R2. In cell-free systems, p53R2 did not oxidize a reactive oxygen species (ROS) indicator carboxy-H2DCFDA, but another class I RR small subunit, hRRM2, did. Further studies showed that purified recombinant p53R2 protein has catalase activity, which breaks down H2O2. Overexpression of p53R2 reduced intracellular ROS and protected the mitochondrial membrane potential against oxidative stress, whereas overexpression of hRRM2 did not and resulted in a collapse of mitochondrial membrane potential. In a site-directed mutagenesis study, antioxidant activity was abrogated in p53R2 mutants Y331F, Y285F, Y49F, and Y241H, but not Y164F or Y164C. The fluorescence intensity in mutants oxidizing carboxy-H2DCFDA, in order from highest to lowest, was Y331F > Y285F > Y49F > Y241H > wild-type p53R2. This indicates that Y331, Y285, Y49, and Y241 in p53R2 are critical residues involved in scavenging ROS. Of interest, the ability to oxidize carboxy-H2DCFDA indicated by fluorescence intensity was negatively correlated with RR activity from wild-type p53R2, mutants Y331F, Y285F, and Y49F. Our findings suggest that p53R2 may play a key role in defending oxidative stress by scavenging ROS, and this antioxidant property is also important for its fundamental enzymatic activity.
 ...
PMID:Structurally dependent redox property of ribonucleotide reductase subunit p53R2. 1648 86

Tetraploidy can result in cancer-associated aneuploidy. As shown here, freshly generated tetraploid cells arising due to mitotic slippage or failed cytokinesis are prone to undergo Bax-dependent mitochondrial membrane permeabilization and subsequent apoptosis. Knockout of Bax or overexpression of Bcl-2 facilitated the survival of tetraploid cells at least as efficiently as the p53 or p21 knockout. When tetraploid cells were derived from diploid p53 and Bax-proficient precursors, such cells exhibited an enhanced transcription of p53 target genes. Tetraploid cells exhibited an enhanced rate of spontaneous apoptosis that could be suppressed by inhibition of p53 or by knockdown of proapoptotic p53 target genes such as BBC3/Puma, GADD45A and ferredoxin reductase. Unexpectedly, tetraploid cells were more resistant to DNA damaging agents (cisplatin, oxaliplatin and camptothecin) than their diploid counterparts, and this difference disappeared upon inhibition of p53 or knockdown of p53-inducible ribonucleotide reductase. Tetraploid cells were also more resistant against UVC and gamma-irradiation. These data indicate the existence of p53-dependent alterations in apoptosis regulation in tetraploid cells.
 ...
PMID:Apoptosis regulation in tetraploid cancer cells. 1667 48


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