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)

In vitro experiments have demonstrated intercellular trafficking of the VP22 tegument protein of herpes simplex virus type 1 from infected cells to neighboring cells, which internalize VP22 and transport it to the nucleus. VP22 also can mediate intercellular transport of fusion proteins, providing a strategy for increasing the distribution of therapeutic proteins in gene therapy. Intercellular trafficking of the p53 tumor suppressor protein was demonstrated in vitro using a plasmid expressing full-length p53 fused in-frame to full-length VP22. The p53-VP22 chimeric protein induced apoptosis both in transfected tumor cells and in neighboring cells, resulting in a widespread cytotoxic effect. To evaluate the anti-tumor activity of p53-VP22 in vivo, we constructed recombinant adenoviruses expressing either wild-type p53 (FTCB) or a p53-VP22 fusion protein (FVCB) and compared their effects in p53-resistant tumor cells. In vitro, treatment of tumor cells with FVCB resulted in enhanced p53-specific apoptosis compared to treatment with equivalent doses of FTCB. However, in normal cells there was no difference in the dose-related cytotoxicity of FVCB compared to that of FTCB. In vivo, treatment of established tumors with FVCB was more effective than equivalent doses of FTCB. The dose-response curve to FVCB was flatter than that to FTCB; maximal antitumor responses could be achieved using FVCB at doses 1 log lower than those obtained with FTCB. Increased antitumor efficacy was correlated with increased distribution of p53 protein in FVCB-treated tumors. This study is the first demonstration that VP22 can enhance the in vivo distribution of therapeutic proteins and improve efficacy in gene therapy.
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PMID:Intratumoral spread and increased efficacy of a p53-VP22 fusion protein expressed by a recombinant adenovirus. 1150 18

Haploid and diploid cell suspensions of Taxus spp. were examined for their adaptive plasticity in response to simulated microgravity, unit gravity, and hypergravity. Cell suspensions produced the taxane, paclitaxel, (TAXOL (R)), which is useful for the treatment of various cancers. Amyloplasts contributed to taxane ring biosynthesis and to drug release at the cell wall. Drug-producing cells reacted as gravisensing osmotic tensiometers. In stressed cells, amyloplasts docked and fused in clusters to sites on the plasmalemma before taxane discharge into the culture medium. In simulated microgravity and compared to all other treatments, taxane production was reduced nearly 100-fold. The percent paclitaxel of total taxanes remained 3-to 6-fold greater, and biomass doubled. When p53-independent programmed cell death was induced, taxanes were released into the culture medium as free molecules (soluble and insoluble) or bound to membranes, nuclear fragments, xylan residues, and other particulate materials. Unit gravity and especially hypergravity promoted xylogenesis and significant drug overproduction. A model relating families of >touch = (TCH), taxane early response (TER), nuclear cycling, and apoptosis-regulating genes to gravisensing, cell wall modifications, and to taxane recovery accounted for most but not all of the observations.
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PMID:Gravisensing, apoptosis, and drug recovery in Taxus cell suspensions. 1154 82

Regulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Here we show that doxorubicin (Dox), a drug used in antitumor therapy, triggered a marked accumulation of p53 and induced CD95 gene expression and apoptosis in proliferating human umbilical vein endothelial cells (HUVECs). Transfection and site-directed mutagenesis experiments using the CD95 promoter fused to an intronic enhancer indicated the requirement for a p53 site for Dox-induced promoter activation. Furthermore, the p53 inhibitor pifithrin-alpha (PFT-alpha) blocked both promoter inducibility and protein up-regulation of CD95 in response to Dox. Up-regulated CD95 in Dox-treated cells was functional in eliciting apoptosis upon incubation of the cells with an agonistic CD95 antibody. However, Dox-mediated apoptosis was independent of CD95/CD95L interaction. The analysis of apoptosis in the presence of PFT-alpha and benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone revealed that both p53 and caspase activation are required for Dox-mediated apoptosis of HUVECs. Finally, Dox triggered Bcl-2 down-regulation, cytochrome c release from mitochondria, and the activation of caspases 9 and 3, suggesting the involvement of a mitochondrially operated pathway of apoptosis. These results highlight the role of p53 in the response of primary endothelial cells to genotoxic drugs and may reveal a novel mechanism underlying the antitumoral properties of Dox, related to its ability to induce apoptosis in proliferating endothelial cells.
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PMID:Doxorubicin induces apoptosis and CD95 gene expression in human primary endothelial cells through a p53-dependent mechanism. 1177 55

The murine homologue of the ATF3 transcription factor increases tumor metastases but, surprisingly, represses 72-kDa type IV metalloproteinase (MMP-2) expression. The current study describes a novel mechanism by which ATF3 regulates transcription. Progressive deletions of the MMP-2 promoter indicated a 38-base pair region (-1659/-1622) necessary for the ATF3-mediated repression. This region lacked CREB/AP-1 motifs but contained a consensus p53 motif shown previously to regulate MMP-2 expression. The activity of a p53 response element-driven luciferase reporter was reduced in ATF3-expressing HT1080 clones. Although MMP-2 promoter activity was not repressed by ATF3 in p53-deficient Saos-2 cells, p53 re-expression increased MMP-2 promoter activity and restored the sensitivity to ATF3. The activity of a GAL4-driven reporter in HT1080 cells co-expressing the full-length p53 sequence fused to the GAL4 DNA binding domain was diminished by ATF3. p53-ATF3 protein-protein interactions were demonstrated both in vivo and in vitro. Cell cycle analysis, performed as an independent assay of p53 function, revealed that gamma-irradiation-induced slowed G(2)/M cell cycle progression (attributable to p53) was countered by ATF3. Thus, ATF3 represses MMP-2 expression by decreasing the trans-activation of this gene by p53.
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PMID:ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter. 1179 11

The p53-family of proteins, including p53, p63, and p73, shares a high degree of structural similarity and can carry out some redundant functions. However, mechanisms that regulate the localization and activity of these proteins have not been fully clarified. In this study, a nuclear localization signal (NLS) was identified in p73, which is required for p73 nuclear import and which could promote the nuclear import of a heterologous, cytoplasmic protein. Mutants lacking the NLS localized to the cytoplasm and displayed diminished transcriptional activity. A nuclear export signal (NES) was also recognized in p73s C terminus, the deletion of which caused p73 to display a more nuclear localization pattern. This NES was sensitive to leptomycin B and could function as an independent export signal when fused to a heterologous protein. Interestingly, p73 mutant proteins lacking the NLS or the NES were more stable than wild-type p73, suggesting that nuclear import and nuclear export are required for efficient p73 degradation. Our results indicate that p73 localization is controlled by both nuclear import and export and suggest that the overall distribution of p73 is likely to result from the balance between these two processes. Proper control of nuclear import and export is likely to be an important regulatory determinant of p73.
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PMID:Nuclear import and export signals in control of the p53-related protein p73. 1184 29

The immediate-early (IE) protein BICP0 of bovine herpesvirus-1 (BHV-1) may have other functions besides transactivation of viral promoters. Recently, we observed that BICP0, delivered to cultured cells by a helpervirus-free amplicon system, forms spherical or doughnut-like structures in which the tumor suppressor protein p53 is sequestered. The objective was to determine whether BICP0 and p53 interact physically, we used both yeast and mammalian two-hybrid systems. As a bait plasmid, pVA3 which encodes a hybrid protein consisting of the Gal4 DNA binding domain fused to murine p53 was used. The BICP0 gene or its truncated versions were inserted into the prey plasmid pGAD424. Bait and prey plasmids were cotransformed into yeast strain Y153, which has LacZ and HIS3 reporter genes under the control of Gal4 upstream activating sequence. After 4-6 days, colonies were stained for beta-galactosidase activity. In the mammalian two-hybrid system, pM-53 was used as a bait where truncated p53 fused to Gal4 DNA binding domain is expressed. The BICP0 gene was cloned into prey plasmid pVP16. The interaction between p53 and SV40 T-antigen was evaluated as a positive control in both systems. Neither full-length BICP0 nor its truncated derivatives induced beta-galactosidase activity in yeast whereas the positive control turned blue under the same conditions. The mammalian two-hybrid system, in which chloramphenicol acetyltransferase (CAT) activity was used as a reporter, also failed to show an interaction between these two proteins. Co-localization of p53 with BICP0 in spherical structures is unlikely to result from a direct physical interaction between these two proteins. Mediation by additional cellular proteins may be required.
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PMID:Search for physical interaction between BICP0 of bovine herpesvirus-1 and p53 tumor suppressor protein. 1188 93

The human polyomavirus JC virus is the etiologic agent of progressive multifocal leukoencephalopathy (PML). As the JC virus early promoter directs cell-specific expression of the viral replication factor large T antigen, transcriptional regulation constitutes a major mechanism of glial tropism in PML. It has been demonstrated that SV40 or JC virus large T antigen interacts with p53 protein and regulates many viral and cellular genes. In this study we found that p53 represses the JC virus early promoter in both glial and nonglial cells. To identify the cis-regulatory elements responsible for p53-mediated repression, deletional and site-directed mutational analyses were performed. Deletion of the enhancer region diminished p53-mediated transcriptional repression. However, point mutations of several transcription factor binding sites in the basal promoter region did not produce any significant changes. In support of this observation, when the enhancer was fused to a heterologous promoter, p53 reduced the promoter activity about three fold. These results indicate that the enhancer region is important for the repression of JC virus transcription by p53. Furthermore, coexpression of JC virus T antigen with a p53 protein abolished p53-mediated repression of the JC virus early promoter in non-glial cells, but not in glial cells. This finding suggests that T antigen interacts with p53 and regulates JC virus transcription in a cell-specific manner.
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PMID:Transcriptional regulation of the glial cell-specific JC virus by p53. 1200 37

The p53 tumor suppressor is a transcription factor that activates the expression of many target genes. We have previously reported the identification of a p53-regulated mouse gene DDA3. The 5' upstream genomic region of the mouse DDA3 was cloned, and sequence analysis revealed the presence of a potential p53 response element (RE2) residing at nucleotides +390 approximately +409 relative to the first translation start site. When fused upstream to a luciferase reporter gene, 5' genomic regions of the DDA3 gene containing RE2 were shown to be responsive to the wild-type, but not mutant p53, in a transient transfection assay. RE2 was sufficient to confer the transactivation responsiveness to p53. Furthermore, gel mobility shift analysis showed that RE2 formed specific complexes with wild-type p53. Induction of DDA3 was found in adriamycin treated normal mouse embryonic fibroblast cells (MEF), but not in p53 knockout (p53(-/-)) MEF. Overexpression of p73 induced DDA3 mRNA expression, and luciferase reporter analysis indicated that RE2 was responsive to transactivation by members of the p73 family proteins. Consistent with these findings, elevated expression of p73 protein and DDA3 mRNA were observed concomitantly in the p53(-/-) MEF cells treated with cisplatin. These results together demonstrated that DDA3 is a transcriptional target gene of p53 and its related-protein p73.
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PMID:Mouse DDA3 gene is a direct transcriptional target of p53 and p73. 1208 36

Fractionation of the crude methanol extract of the ascidian Cystodytes dellechiajei collected in Brazil yielded two novel alkaloids, sebastianine A (1) and sebastianine B (2). The structures of both 1 and 2 were established by analysis of spectroscopic data, indicating an unprecedented ring system for both compounds, comprising a pyridoacridine system fused with a pyrrole unit in sebastianine A (1) and a pyridoacridine system fused with a pyrrolidine system condensed with alpha-hydroxyisovaleric acid in sebastianine B (2). Both alkaloids displayed a cytotoxic profile against a panel of HCT-116 colon carcinoma cells indicative of a p53 dependent mechanism.
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PMID:Sebastianines A and B, novel biologically active pyridoacridine alkaloids from the Brazilian ascidian Cystodytes dellechiajei. 1212 46

Specificity in the immune system is dictated and regulated by specific recognition of peptide/major histocompatibility complexes (MHC) by the T cell receptor (TCR). Such peptide/MHC complexes are a desirable target for novel approaches in immunotherapy because of their highly restricted fine specificity. Recently a potent anti-human p53 CD8(+) cytotoxic T lymphocyte (CTL) response has been developed in HLA-A2 transgenic mice after immunization with peptides corresponding to HLA-A2 motifs from human p53. An alpha/beta T-cell receptor was cloned from such CTL which exhibited a moderately high affinity to the human p53(149-157) peptide. In this report, we investigated the possibility of using a recombinant tumor-specific TCR for antigen-specific elimination of cells that express the specific MHC-peptide complex. To this end, we constructed a functional single-chain Fv fragment from the cloned TCR and fused it to a very potent cytotoxic molecule, a truncated form of Pseudomonas exotoxin A (PE38). The p53 TCR scFv-P38 fusion protein was generated by in vitro refolding from bacterially-expressed inclusion bodies, and was found to be functional by its ability to bind antigen-presenting cells (APC) which express the specific p53-derived peptide. Moreover, we have shown that the p53-specific TCR scFv-PE38 molecule specifically kills APC in a peptide-dependent manner. These results represent the first time that a TCR-derived recombinant single-chain Fv fragment has been used as a targeting moiety to deliver a cytotoxic effector molecule to cells and has been able to mediate the efficient killing of the particular cell population that expresses the specific MHC/peptide complex. Similarly to antibody-based targeting approaches, TCR with tumor cell specificity represent attractive candidates for generating new, very specific targeting moieties for various modes of cancer immunotherapy.
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PMID:A functional recombinant single-chain T cell receptor fragment capable of selectively targeting antigen-presenting cells. 1238 8


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