UNIPROT:P04637 - FACTA Search

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

The p53 family of transcription factors plays a pivotal role in the control of the cellular response to DNA damaging agents. In addition to pro-apoptotic molecules such as p53, TAp73 and TAp63, this gene family also encodes for the anti-apoptotic molecules deltaNp73, deltaNp63, deltaNp53, and p53 mutants are often found in tumor cells, that have the role to limit and to modulate the pro-apoptotic side of the family. The ratio between the different members of the family is critical to make the life or death decision following DNA damage and is tightly regulated by post-translational and transcriptional mechanisms. In this study we have uncovered a novel positive feedback that involves the transcriptional activation of the anti-apoptotic molecule deltaNp63 by the anti-apoptotic molecules deltaNp73 and mutant p53, and that is put into motion upon treatment with a subset of DNA damaging agents such as Doxorubicin and 5-FU. DeltaNp73 and mutant p53 associate with the deltaNp63 promoter inducing its transcription and this is enhanced by doxorubicin treatment. Furthermore we have observed that deltaNp73- and mutp53-mediated activation of the deltaNp63 promoter requires the functionality of the proximal CCAAT boxes of this promoter, being hampered by mutation of CCAAT boxes or by dominant negative NFYA expression. This mechanism may serve as an additional control of the response of a normal cell to DNA damage or as an anti-apoptotic barrier of cancer cells subjected to DNA damage.
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PMID:Cross-talks in the p53 family: deltaNp63 is an anti-apoptotic target for deltaNp73alpha and p53 gain-of-function mutants. 1693 14

In Europe, swainsonine has been studied widely for prevention of metastasis and cancer therapy. In order to investigate the effects and mechanisms of swainsonine on the human gastric carcinoma SGC-7901 cell, we carried out in vivo and in vitro experiments. After treatment with swainsonine, an effective dose and IC50 value of swainsonine for SGC-7901 cells were examined by MTT assay. Cell-cycle distribution and apoptotic rates were analyzed using FCM, and [Ca2+]i was measured using LSCM. The expression of p53, c-myc and Bcl-2 were determined using an immunocytochemical method. Simultaneously, 50 mice were divided randomly into five groups. Three groups were administrated swainsonine at dose of 3, 6 and 12 mg/kg body wt., two control groups were administrated N.S. 20 ml/kg body wt. and 5-Fu 20 mg/kg body wt., respectively, by intraperitoneal injection. The inhibition rate was calculated and pathological sections were observed. The growth of SGC-7901 cell is inhibited by swainsonine in vitro, with an IC50 value at 24 h of 0.84 microg/ml, and complete inhibition concentration is 6.2 microg/ml. After treatment with swainsonine at the concentrations of 0.5, 1.5 and 4.5 microg/ml for 24 h, the expression of apoptosis inhibiting gene p53 and bcl-2 decreases, and the apoptotic trigger gene c-myc increases markedly (p<0.05), as well as [Ca2+]i overloading, SGC-7901 cell is induced to apoptosis in the end. It is also found that the percentages of S phase are 38.8%, 39.7% and 29.6%, respectively (20.0% in control group and 23.2% in 5-Fu group). The rates of inhibition were 13.2%, 28.9%, 27.3%, respectively, when the nude mice were administered swainsonine (p<0.05 or 0.01). The structure of the tumor showed hemorrhage, necrosis and inflammatory cell infiltration. We therefore conclude that swainsonine could inhibit cell proliferation in vitro and the growth of human gastric carcinoma in vivo. The mechanisms of swainsonine-induced apoptosis may relate to [Ca2+]i overloading and the expression of apoptosis-related genes.
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PMID:Inhibition of the growth of human gastric carcinoma in vivo and in vitro by swainsonine. 1709 81

While interferon-alpha (IFN-alpha) subtypes share a common specific receptor composed of two subunits, interferon-alpha receptor (IFNAR)-1 and IFNAR-2, their subtype activities are exhibited via several intracellular signaling pathways and thus subsequently show different biological effects. Anti-proliferative effects of single treatment with IFN-alpha subtypes or 5-fluorouracil (FU), and of combined treatment with each IFN-alpha subtype and 5-FU were examined on three hepatocellular carcinoma cell lines, HepG2, HLE and PLC/PRF/5. HepG2 and PLC/PRF/5 cells were susceptible to the combination treatment, but HLE cells were not. Proliferation of PLC/PRF/5 cells was also inhibited by the IFN-alpha subtypes singly. In addition, apoptosis was observed in HepG2 cells upon treatment with 5-FU alone and with the combination treatment, and in PLC/PRF/5 cells after single treatment with the IFN-alpha subtypes and after the combination treatment. IFN-alpha subtypes induced cell cycle arrest in the G2/M phase in HepG2 and PLC/PRF/5. Analyses by Western blotting and immunoprecipitation revealed increased p53 phosphorylation in HepG2 and PLC/PRF/5 cells but not in HLE cells after combined treatment. Single treatment with IFN-alpha subtypes promoted p53 activation only in PLC/PRF/5 cells. These results propose that IFN-alpha subtypes induce cells to undergo apoptosis through p53 activation directly and indirectly, in collaboration with 5-FU, further suggesting the presence of distinct signal pathways for IFN-alpha-induced apoptosis.
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PMID:Role of p53 in the inhibitory effects of interferon-alpha subtypes on proliferation of hepatocellular carcinoma cells. 1709 86

Multimodal treatment protocols are increasingly employed to improve the survival of patients with locally advanced adenocarcinomas of the upper gastrointestinal tract, however, only 30-40% per year of the patients respond to 5-FU and cisplatin-based neoadjuvant chemotherapy. The goal of our studies is the identification of reliable genetic markers, on the genomic DNA-level, mRNA, or protein level that could predict response of upper gastrointestinal carcinomas prior to neoadjuvant chemotherapy. In esophageal carcinomas, a higher gene expression of methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism, was more frequently found in responding patients. In addition high gene expression of caldesmon and of the two drug carrier proteins, MRP1 and MDR1 was associated with response to therapy. By performing a genome-wide profiling on the protein level in a small group of patients, new potential markers were identified, which have to be validated in ongoing studies. In gastric carcinomas, mutations of the p53 gene revealed no association with response or survival, but tumors with a high rate of loss of heterozygosity (LOH), determined by microsatellite analysis, showed a better response to a cisplatin-based chemotherapy. Analysis of expression of 5-FU-(e.g., TS, DPD, and TP) and cisplatin-(e.g., ERCC1, ERCC4, GADD45A, and KU80) related genes, demonstrated an association of DPD expression with response and survival. The combined consideration of TP and GADD45 gene expression, showed the most obvious association with therapy response in this tumor. Our studies point to promising markers with potential use for chemotherapy response prediction of adenocarcinomas of the upper gastrointestinal tract, but prospective studies for validation are necessary.
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PMID:Prediction of response to neoadjuvant chemotherapy in carcinomas of the upper gastrointestinal tract. 1716 61

Study effect and mechanisms of growth-suppression of hepatocelluar carcinoma (HCC) in nude mice. The construction of the pAdeasy-1-pTrack-CMV-hIL-24 recombined adenovirus vector (Ad-hIL-24) was completed and lineared with PacI. Ad-hIL-24 were transfected into QBI-293 cells and obtained. 16 nude mice of the subcutaneous tumor models were established with SMMC-7721 HCC and were randomly divided into NS, 5-Fu, Ad and Ad-hIL-24 groups. Then 100 microL NS, Ad (10(7) pfu) and Ad-hIL-24 (10(7) pfu) for each one were given respectively QOD, and 5-Fu (20 microg/kg) were injected Q.D., for 5 times, with intratumor injections. After 15 d, 16 mice were sacrificed and subcutaneous tumors were taken out. The volumes (before administration, 1 week and 2weeks after administration) were measured and the weights of tumor were weighed and ratios of tumor-suppression were calculated. The morphological changes of apoptotic tumor cells were observed under microscope. Caspase3, P53 and P27, CD34 and VEGF were tested in immunohistochemistry. In tumor subcutaneous model, compared with NS group, the ratios of tumor-suppression of Ad-hIL-24 group and 5-Fu group were 68.52% (P < 0.01) and 65.64 (P < 0.01), respectively. Caspase3 protein in Ad-hIL-24 group was higher than other 3 groups significantly (P < 0.01). The expression of P27 also differed from NS group (P < 0.01). CD34 and VEGF protein in Ad-hIL-24 group can inhibit neovascularization obviously (P < 0.001), compared with NS and Ad groups. Ad-hIL-24 inhibits the growth of SMMC-7721 HCC on nude mice's. The mechanisms of tumor-suppression may be multi-pathways such as the induction of caspase3 pathway, P27 activities and the antiangiogenic mechanism.
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PMID:[The study of the growth-suppression and mechanisms of hepatocelluar carcinoma tumor in nude mice]. 1716 14

Approximately 50% of protein and RNA synthesis in proliferating cells are devoted to ribosomal biogenesis. Coordination between ribosome biogenesis, growth, and proliferation is critical for maintenance of homeostasis and tumor suppression. Aberrant rRNA expression and processing is sensed by p53. Ribosomal stress increases the binding between MDM2 and ribosomal proteins L5, L11, and L23, resulting in p53 stabilization. Our recent study showed that p53 activation by ribosomal stress also involves degradation of MDMX in an MDM2-dependent fashion. Failure to eliminate MDMX due to overexpression results in the sequestration of p53 into inactive complexes, severely impairing p53-dependent cell cycle arrest during ribosomal stress. Furthermore, MDMX overexpression promotes resistance to the chemotherapeutic agent 5-FU, which at low concentrations activates p53 by inhibiting RNA metabolism. Therefore, MDMX is an important regulator of p53 response to ribosomal stress. MDMX overexpression in tumors may significantly influence response to chemotherapy agents that target rRNA biogenesis.
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PMID:Distinct roles of MDMX in the regulation of p53 response to ribosomal stress. 1732 2

Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors.
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PMID:Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. 1733 91

5-Fluorouracil, usually in combination with folinic acid, is widely used in the treatment of both colorectal and head and neck squamous cell cancer patients. Since 5-fluorouracil plus folinic acid and the antifolate thymidylate synthase inhibitor; raltitrexed have distinct mechanisms of action and toxicity profiles, we have evaluated the potential synergistic antitumor interaction between these two agents combined with a sequential schedule of administration in KB (wt-p53) and Cal27 (mut-p53) head and neck squamous cell carcinomas, and LoVo (wt-p53) and HT29 (mut-p53) colorectal cell lines. The combination between a 24-h exposure to raltitrexed followed by a 4-h exposure to 5-fluorouracil plus folinic acid was globally synergistic, as assessed by the median effect principle and combination index. A specific contribution of folinic acid to the cytotoxic effect of the raltitrexed/5-fluorouracil combination was clearly demonstrated by the evaluation of the potentiation factor. In all cell lines, a 1.5- up to 17-fold reduction in the IC50 of both raltitrexed and 5-fluorouracil plus folinic acid was observed in the combination setting compared with the concentrations of the each drug used alone. Moreover, we demonstrated that raltitrexed/5-fluorouracil plus folinic acid induced a distinct S-phase block of the cell cycle, as well as a potentiation of the apoptotic cell death, compared with 5-fluorouracil plus folinic acid or raltitrexed/5-fluorouracil combination. This preclinical work represents, at least to our knowledge, the first demonstration of a synergistic interaction between raltitrexed and 5-fluorouracil modulated by folinic acid, and could represent a rationale for further clinical investigation of raltitrexed/5-fluorouracil plus folinic acid combination.
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PMID:Synergistic antitumour effect of raltitrexed and 5-fluorouracil plus folinic acid combination in human cancer cells. 1758

Cyr61/CCN1 is a secreted extracellular matrix associated protein involved in diverse biological functions and plays multiple roles in tumorigenesis. Cyr61 was down-regulated in HCC tumor tissues as observed in our previous cDNA microarray study, but its potential role in hepatocarcinogenesis is still unclear. To explore the biological significance of Cyr61 in HCC development, over-expression of this gene was established in HCC cell lines and its effects on cell proliferation, adhesion, migration and invasion were analyzed in this study. Cyr61 expression was down-regulated in HCC tumors as measured by quantitative real-time PCR and its protein level was decreased in most HCC cell lines as detected by Western blot. Over-expression of Cyr61 in HCC cell lines suppressed cell proliferation in monolayer and anchorage-independent growth in soft agar, whereas down-regulation of Cyr61 by siRNA increased cell proliferation rate. Over-expression of Cyr61 also significantly enhanced adhesion activities of HepG2 cells to various ECM proteins. Moreover, stably transfected HepG2-Cyr61 cells showed inhibited cell mobility (40-45%) and reduced invasiveness (30-40%) compared to HepG2-Neo controls. Furthermore, upon exposure to 5-Fluorouracil and UV irradiation, Cyr61 was rapidly induced in both p53(+/+) HepG2 and p53(-/-) Hep3B cells. However, only HepG2 cells showed increased G2/M phase arrest with concomitant up-regulation in p53 and p21 levels, suggesting that Cyr61 may play an active role in regulating HCC cell growth involving p53 as well as alternative pathways. In conclusion, we demonstrated that Cyr61 is a tumor suppressor in hepatocarcinogenesis and is involved in DNA damage response.
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PMID:Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response. 1769 98

When normal cells come under stress, the wild-type (WT) p53 level increases resulting in the regulation of gene expression responsible for growth arrest or apoptosis. Here we show that elevated levels of WT p53 or its homologue, p73, inhibit expression of a number of cell cycle regulatory and growth promoting genes. Our analysis also identified a group of genes whose expression is differentially regulated by WT p53 and p73. We have infected p53-null H1299 human lung carcinoma cells with recombinant adenoviruses expressing WT p53, p73 or beta-galactosidase, and have undertaken microarray hybridization analyses to identify genes whose expression profile is altered by p53 or p73. Quantitative real-time PCR verified the repression of E2F-5, centromere protein A and E, minichromosome maintenance proteins (MCM)-2, -3, -5, -6 and -7 and human CDC25B after p53 expression. 5-Fluorouracil treatment of colon carcinoma HCT116 cells expressing WT p53 results in a reduction of the cyclin B2 protein level suggesting that DNA damage may indeed cause repression of these genes. Transient transcriptional assays verified that WT p53 repressed promoters of a number of these genes. Interestingly, a gain-of-function p53 mutant instead upregulated a number of these promoters in transient transfection. Using promoter deletion mutants of MCM-7 we have found that WT p53-mediated repression needs a minimal promoter that contains a single E2F site and surrounding sequences. However, a single E2F site cannot be significantly repressed by WT p53. Many of the genes identified are also repressed by p21. Thus, our work shows that WT p53 and p73 repress a number of growth-related genes and that in many instances this repression may be through the induction of p21.
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PMID:Wild-type p53 and p73 negatively regulate expression of proliferation related genes. 1798 88

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