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

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

We investigated the effect of pifithrin-alpha (PFTalpha), a chemical inhibitor of p53, on DNA double-strand break (DSB) repair in mammalian chromosomes. Thymidine kinase-deficient mouse fibroblasts were stably transfected with DNA substrates containing one or two recognition sites for yeast endonuclease I-SceI embedded within a herpes simplex virus thymidine kinase gene. Genomic DSBs were induced by introducing an I-SceI expression plasmid into cells in the presence or absence of 20 microM PFTalpha. From cells containing the DNA substrate with a single I-SceI site we recovered low-fidelity nonhomologous end-joining (NHEJ) events in which one or more nucleotides were deleted or inserted at the DSB. From cells containing the substrate with two I-SceI sites we recovered high-fidelity DNA end-joining (precise ligation (PL)) events. We found that treatment of cells with PFTalpha caused a 5-10-fold decrease in recovery of PL but decreased recovery of NHEJ by less than two-fold. Deletion sizes associated with NHEJ were unaffected by treatment with PFTalpha. Our work suggests the possibility that p53 facilitates high-fidelity DSB repair while playing little or no role in mutagenic NHEJ.
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PMID:Suppression of high-fidelity double-strand break repair in mammalian chromosomes by pifithrin-alpha, a chemical inhibitor of p53. 1250 64

The advent of advanced cell culture and cytogenetics techniques in the 1950s opened a new avenue for research on the pathogenic interactions between animal viruses and their hosts. Studies of many viruses revealed their ability to nonspecifically induce cytogenetic damage to their host cell's chromosomes. However, only three viruses, the oncogenic adenoviruses, herpes simplex virus (HSV) and human cytomegalovirus (HCMV), have been found to cause non-random, site-specific chromosomal damage. Adenovirus (Ad) type 12 induces fragility at four distinct loci (RNU1, RNU2, RN5S and PSU1) in many different types of human cells. A common feature of these loci is that they contain a repeated array of transcriptionally active genes encoding small structural RNAs. Site-specific induction of breaks also requires the virally encoded E1B protein of M(r) 55000 and the C-terminus of the cellular p53 protein. Analysis of the induction of damage by HSV and HCMV necessitates consideration of several factors, including the strain of virus used, the timing of infection, the type of cell used, and the multiplicity of infection. Both HSV strains 1 and 2 are cytotoxic, although the former seems to be more proficient at inducing damage. At early times post infection, HSV induces breaks and specific uncoiling of the centromeres of chromosomes 1, 9 and 16. This is followed at later times by a more complete severing of all of the chromosomes, termed pulverisation. Damage by HSV requires viral entry and de novo viral protein synthesis, with immediate early viral proteins responsible for the induction of breaks and uncoiling and early gene products (most likely nucleases) involved in the extensive pulverisation seen later. HCMV has been studied primarily in permissive human fibroblasts. Its ability to induce specific damage in chromosome 1 at two loci, 1q21 and 1q42, was only recently revealed as the cells must be in S-phase when they are infected for the breaks to be observed. In contrast to adenovirus and HSV, HCMV induction of specific breakage requires only viral entry into the cell and not de novo viral protein expression. This latter point may be a factor in its ability to cause damage in the developing fetal brain, where the most severe clinical manifestations of congenital infection are observed.
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PMID:Viral induction of site-specific chromosome damage. 1251 60

Protein-protein interactions control essential steps in signal transduction pathways and other intracellular processes, and assembly of protein complexes modulates and responds to the regulatory events that exist in living animals. We have used microPET and fluorescence imaging to detect interactions between p53 tumor suppressor and large T antigen (TAg) of SV40 virus in a tetracycline-inducible two-hybrid system. To additionally validate this molecular imaging technique, we investigated whether expression of the reporter gene, comprised of a mutant thymidine kinase from herpes simplex virus 1 fused to green fluorescent protein could quantify relative differences in amounts of interacting hybrid proteins. In HeLa cells stably transfected with the reporter gene and interacting (p53-TAg) or noninteracting (p53 and polyoma virus coat protein) pairs of proteins, treatment with doxycycline produced time- and dose-dependent increases in expression of hybrid proteins. Proportional increases in amounts of reporter gene were produced only in cells expressing p53 and TAg. In mice bearing xenografts of these stably transfected HeLa cells, amounts of hybrid proteins were regulated with doxycycline. Both microPET imaging and biodistribution studies showed time- and dose-dependent increases in accumulation of the reporter substrate 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine only in p53-TAg tumors. Fluorescence microscopy of excised tumors also showed corresponding changes in expression of the fusion reporter gene in response to binding of p53 and TAg. These data demonstrate that the imaging two-hybrid system responds in a proportional fashion to increasing amounts of interacting proteins in vivo.
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PMID:Molecular imaging of protein-protein interactions: controlled expression of p53 and large T-antigen fusion proteins in vivo. 1270 63

In order to determine the ability of bovine herpesvirus type 1 (BHV-1) to suppress apoptosis, we examined the effects of BHV-1 infection on sorbitol-induced apoptosis on Madin-Darby bovine kidney (MDBK) cells. BHV-1 suppresses sorbitol-induced apoptosis in a manner similar to that of herpes simplex virus type 1 (HSV-1), indicating that BHV-1 has one or more anti-apoptotic genes. To elucidate the molecular mechanisms of apoptosis, expression of some genes encoding apoptosis-inhibiting and -promoting factors were analyzed on BHV-1 infected cells during the process of sorbitol-induced apoptosis. Our results revealed that the expression of bcl-2 and bcl-x(L) decreased after 5 and 3 h p.i., respectively; while bax and procaspase-3 expression increased with respect to control as a function of p.i. times and at 7 h p.i. they were not observed. We further show that the expression of p53 gene was also enhanced, suggesting that this apoptotic mechanism is p53 dependent. From these results, we propose that BHV-1 has one or more genes encoding apoptosis-inhibiting factors which interfere with the involvement of bcl-2 gene family members and apoptotic pathway, depending upon caspase-3, triggered by sorbitol.
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PMID:Interference of bovine herpesvirus 1 (BHV-1) in sorbitol-Induced apoptosis. 1270

Herpes simplex virus type 1 regulatory protein ICP0 contains a zinc-binding RING finger and has been shown to induce the proteasome-dependent degradation of a number of cellular proteins in a RING finger-dependent manner during infection. This domain of ICP0 is also required to induce the formation of unanchored polyubiquitin chains in vitro in the presence of ubiquitin-conjugating enzymes UbcH5a and UbcH6. These data indicate that ICP0 has the potential to act as a RING finger ubiquitin ubiquitin-protein isopeptide ligase (E3) and to induce the degradation of certain cellular proteins through ubiquitination and proteasome-mediated degradation. Here we demonstrate that ICP0 is a genuine RING finger ubiquitin E3 ligase that can interact with and mediate the ubiquitination of the major oncoprotein p53 both in vitro and in vivo. Ubiquitination of p53 requires ICP0 to have an intact RING finger domain and occurs independently of its ability to bind to the ubiquitin-specific protease USP7.
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PMID:The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and Ubiquitinates p53. 1285 95

Selective killing of tumor cells is an important goal for cancer therapeutics. The tumor suppressor transcription factor p53 is absent or mutated in more than 50% of human tumors. Thus, determining approaches that use p53 status to regulate therapy may be an important strategy for attaining cancer selectivity. We have shown previously that a designed transcriptional repressor, K2-5F, strongly and selectively reduces the expression of its target gene MDR1. In this study, we exploited p53 status and the strong repressor activity of K2-5F to establish a system for preferential killing of p53-negative cells. In this system, the expression of K2-5F is induced by p53 in normal cells, and the K2-5F repressor then inhibits the expression of herpes simplex virus thymidine kinase (HSV-TK) driven by an MDR1 minipromoter. In p53-deficient cells, little K2-5F is expressed, and thus HSV-TK is expressed, allowing the cells to be killed by ganciclovir (GCV). K2-5F induced by exogenous p53 dramatically reduced the expression of HSV-TK in human embryonic kidney 293 cells, and it subsequently increased cell survival in response to GCV. To further evaluate this approach in a uniform genetic background, we developed Saos-2 cells stably expressing physiological levels of p53 and paired them with wild-type p53-negative Saos-2 cells. Stable expression of moderate levels of p53 in Saos-2 cells was able to induce the expression of K2-5F and reduce HSV-TK expression and resulted in a modest but distinct protection from GCV toxicity. Thus, this system may be suitable for further development as an approach to selective cancer therapy.
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PMID:P53-dependent cell-killing by selective repression of thymidine kinase and reduced prodrug activation. 1286 33

Midkine (MK) is preferentially expressed in a number of human tumors, while the expression in adult normal tissues is restricted. Previous studies showed that a 2.3-kb regulatory region of the human MK gene could selectively activate a linked suicide gene in tumors. In this study, we explored the minimal promoter region using genomic fragments deleted from the 5'-upstream side and analyzed the mechanism of the preferential activation in tumor cells. Luciferase assays showed that the 0.3-kb fragment from the transcription start site contained a cis-acting element(s) for the promoter activity. Expression of the herpes simplex virus-thymidine kinase gene under the control of the MK promoter followed by ganciclovir administration produced antitumor effects in vivo. Transfection of the wild-type p53 gene into the immortalized fibroblasts bearing mutated p53 and tumor cell lines, which induced cell cycle arrest, decreased the MK promoter-mediated transcription more effectively than the SV40 or the cytomegalovirus promoter-mediated transcription. The P53-mediated downregulation of the MK promoter activity was stronger in p53-defective tumors than in wild-type p53-bearing tumors. Moreover, the MK promoter-mediated luciferase activity was greater in p53-deficient mouse embryonic fibroblasts than in those bearing wild-type p53 gene. The transcriptional activity of the MK promoter could be regulated by cell growth and in part P53-dependent pathways.
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PMID:Cell growth- and P53-dependent transcriptional activity of the midkine promoter confers suicide gene expression in tumor cells. 1288 97

Retrovirally expressed interleukin-2 gene, granulocyte macrophage-colony stimulating factor gene, herpes simplex virus-thymidine kinase gene and p53 gene in human esophageal cancer cells showed antitumor effects in a nude mice xenotransplant model. We established a clinical protocol of gene therapy for advanced esophageal cancer using the wild type p53 gene with an adenovirus vector. In December of 2000, we began the first tumor suppressor gene therapy trial. Now, this trial, which has 9 patients. There have been no serious adverse event excluding fever and local pain. The feasibility of this treatment appears fairly good in these 9 cases. Furthermore, we developed a new method for transducing genes without a virus vector since a virus vector has several potentially unwanted properties. In vivo electroporation is a useful strategy for cancer gene therapy. Moreover, electric pulse to established solid tumors increases intracellular concentrations of chemotherapeutic agents. Transduction of the wild-type p53 gene by electroporation decreased the amount of nedaplatin required for tumor suppression. Electrochemo-gene therapy is a relatively simple method and can produce a better therapeutic effect.
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PMID:[Progress of gene therapy for esophageal cancer in Japan]. 1289 8

Many cancer cells refractory to radiation treatment and chemotherapy proliferate because of loss of intrinsic programmed cell death (apoptosis) regulation. Consequently, the resolution of these cancers are many times outside the management capabilities of conventional therapeutics. We now report that replication-defective delta27 herpes simplex virus (rd delta27) triggers apoptosis in three representative transformed human cell lines. Susceptibility to virus-induced cell death is dependent on the abundance and distribution of modified p53 protein in the tumor cells indicating specific targeting of the treatment. Primary human and mouse fibroblast cells that produce modified p53 are resistant to rd delta27 killing but not to apoptosis induced by nonviral environmental factors. These results suggest that induction of apoptosis by nonreplicating virus is a feasible genetic therapy approach for killing human cancer cells. Our findings may have important implications in designing novel virus-based anticancer strategies in appropriate animal model systems.
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PMID:Viral oncoapoptosis of human tumor cells. 1290 Jul 58

The cytotoxicity of extracellular amyloid beta peptide (Abeta) has been clearly demonstrated in many cell types. In contrast, primary human neurons in culture are resistant to extracellular Abeta-mediated toxicity. Here, we investigate the involvement of p75 neurotrophin receptor (p75NTR) in Abeta-treated human neurons. We find that Abeta1-40 and Abeta1-42, but not the reverse control peptide, Abeta40-1, rapidly increase the levels of p75NTR in a specific and dose-dependent manner. In contrast to observations in cell lines, enhanced expression of p75NTR in human neurons via a herpes simplex virus amplicon vector does not increase the susceptibility of neurons to Abeta. Unexpectedly, inhibition of p75NTR expression with an antisense expression construct or incubation of the cells with an antibody to the extracellular domain of p75NTR sensitizes human neurons to extracellular nonfibrillar or fibrillar Abeta1-42 cytotoxicity. Unlike intracellular Abeta, extracellular Abeta toxicity is independent of p53 and Bax activity. However, Abeta toxicity is inhibited by caspase inhibitors and the glycogen synthase kinase 3beta inhibitor lithium. Neuroprotection against Abeta is phosphatidylinositide 3-kinase dependent but Akt independent. These results are consistent with a neuroprotective role for p75NTR against extracellular Abeta toxicity in human neurons.
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PMID:p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid beta peptide cytotoxicity. 1291 74


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