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)

Replication-restricted herpes simplex virus-1 (HSV-1) strains lacking ICP34.5 are emerging as powerful anticancer agents against several solid tumors including epithelial ovarian cancer (EOC). Although chemotherapy-resistant tumors would be likely candidates for treatment with HSV-1 mutants lacking ICP34.5, the efficacy of these mutants on such tumors is unknown. In the present study, we investigated whether chemotherapy resistance affects the response of ovarian cancer cells to HSV-R3616, an ICP34.5-deficient, replication-restricted HSV-1. Primary EOC cultures obtained from patients who varied in their responses to platinum/paclitaxel induction chemotherapy displayed similar sensitivity to HSV-R3616. Similarly, chemotherapy-sensitive ovarian cancer cells A2780 and PA-1, possessing wild-type p53, and their respective chemotherapy-resistant clones A2780/200CP, lacking p53 function, and PA-1/E6, permanently expressing the HPV E6 gene, were equally sensitive to HSV oncolysis. Because wild-type HSV can kill cells by apoptosis and nonapoptotic mechanisms, we investigated the involvement of apoptosis and the role of the p53 tumor suppressor gene in oncolysis induced by HSV-R3616. Infection of ovarian cancer cell lines by HSV-R3616 was followed by cell death via apoptosis or nonapoptotic mechanisms as noted by morphology, cell cycle analysis, and in situ TUNEL assay. p53 protein levels remained unchanged, and Bax protein levels decreased in cells possessing intact p53 and that mainly underwent HSV-induced apoptosis. Loss of p53 function did not affect the frequency or rate of apoptosis or the sensitivity of EOC cells to the oncolytic effect of HSV-R3616. These results suggest that recombinant HSV-1 lacking ICP34.5 is capable of killing ovarian cancer cells that lack p53 function, resist apoptosis, and/or are chemotherapy resistant. These data support the hypothesis that HSV-based oncolytic therapy may be efficacious in chemotherapy-resistant tumors, including tumors that are deficient in p53.
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PMID:Oncolytic herpes simplex virus-1 lacking ICP34.5 induces p53-independent death and is efficacious against chemotherapy-resistant ovarian cancer. 1095 22

We examined whether antitumor effect could be produced by retrovirally expressed interleukin-2(IL-2) gene, glanulocyte macrophage-colony stimulating factor(GM-CSF) gene, herpes simplex virus-thymidine kinase(HSV-tk) gene and p53 gene in human esophageal cancer cells using nude mice. Loss of tumorigenicity of IL-2 or GM-CSF producing cancer cells were observed. The antitumor effect was also evidenced by the injection of these cells into established tumors of wild-type cells. In suicide gene therapy on esophageal cancer, the growth suppression of esophageal cancer cells transducing HSV-tk gene tumors in nude mice induced by ganciclovir treatment and all the tumors disappeared. The wild-type p53 transduced tumor cells became markedly susceptible to irradiation and anticancer agents. Administration of cisplatine noticeably suppressed the growth of p53 transduced tumors inoculated in nude mice. We established the clinical protocol of gene therapy for esophageal cancer using wild-type p53 gene with adenovirus vector. In this autumn we are going to start this clinical trial.
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PMID:[The protocol of clinical trial and basic experiments for esophageal cancer using gene transduction]. 1100 29

Homologous recombination was examined in cells infected with herpes simplex virus type I. Circular and linear DNA with directly repeated sequences was introduced as recombination substrates into cells. Recombination was measured either by origin-dependent amplification of recombination products or by recombination-dependent expression of luciferase from a disrupted gene. Homologous recombination in baby hamster kidney cells converted linear DNA to circular templates for DNA replication and luciferase expression in the complete absence of virus. The products of homologous recombination were efficiently amplified by the viral replication apparatus. The efficiency of recombination was dependent on the structure of the substrate as well as the cell type. Linear DNA with the direct repeats at internal positions failed to recombine in Balb/c 3T3 cells and induced p53-dependent apoptosis. In contrast, linear DNA with directly repeated sequences precisely at the ends recombined and replicated in 3T3 cells. Homologous recombination in baby hamster kidney cells did not depend on the position of the repeated sequences. We conclude that homologous recombination is independent of viral gene functions and that it is likely to be carried out by cellular proteins. We suggest that homologous recombination between directly repeated sequences in the linear herpes simplex virus type 1 chromosome may help to avoid p53-dependent apoptosis and to promote viral DNA replication.
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PMID:Recombination during early herpes simplex virus type 1 infection is mediated by cellular proteins. 1106 1

To understand the mechanism of neuronal apoptosis induced by herpes simplex virus (HSV) infection in vivo, the distribution of viral antigen, the appearance of apoptotic bodies, and the expressions of the tumor suppressor gene p53 and several transcription factors such as c-fos, c-jun and NF-kappaB were examined immunohistochemically and histopathologically after corneal infection of mice with HSV type 2 strain 186. Five days after HSV infection, viral antigen was diffusely detected in the corneal epithelium, the trigeminal ganglion and the pars caudalis of the spinal trigeminal nucleus. Neuronal apoptosis was observed in the brain stem ipsilateral to the HSV-infected side with the immunoreactivities of c-fos, c-jun, NF-kappaB and p53. Dual-labeling immunohistochemical studies revealed that almost all of the viral antigen-positive neurons and glia in the brain stem also showed p53 immunoreactivity. On the other hand, no neuronal apoptosis but only with the expression of c-jun was found in the trigeminal ganglion. Our results suggest that the different expression of transcription factors between the brain stem and the trigeminal ganglion may influence the neuronal apoptosis induced by HSV infection.
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PMID:Corneal infection of herpes simplex virus type 2--induced neuronal apoptosis in the brain stem of mice with expression of tumor suppressor gene (p53) and transcription factors. 1107 16

Although the mortality and incidence of cervical cancer have been decreasing, those of uterine-body, or endometrial, cancer have been increasing. The proportion of endometrial cancer was reported to have become 33.6% of primary uterine cancers in 1995. Infection with certain types of human papilloma virus (HPV) is considered to be etiologically important for the occurrence of cervical cancer. Because HPV is sexually transmitted, some risk factors for cervical cancer are associated with certain kinds of sexual behavior such as a young age at first intercourse, multiple partners, and infrequent use of barrier-type contraceptives such as condoms. Frequent conceptions and deliveries and histories of sexually transmitted diseases like infection with herpes simplex virus type 2 or chlamydia also have been suggested to be associated with the risk of cervical cancer. Smoking habits and infrequent intake of vegetables and fruits may be related to the increased risk of cervical cancer by supporting persistent infection of HPV through impaired immunological function. Although host factors such as a variant of a tumor suppressor gene like p53 have been assessed in terms of the risk of cervical cancer, these are not yet clearly elucidated. Estrogen stimulation of the endometrium unopposed by progesterone stimulation, namely, unopposed estrogen stimulation, is thought to be involved in the etiology of endometrial cancer. Frequent intake of animal fat, obesity or being overweight, infertility, and histories of diabetes mellitus, hypertension, and polycystic ovary syndrome have been reported to be risk factors for endometrial cancer, and they are thought to increase unopposed estrogen stimulation. Estrogen replacement therapy for postmenopausal symptoms, tamoxifen therapy for breast cancer, and taking sequential-type oral contraceptives have been shown to be exogenous risk factors for endometrial cancer in that they increase unopposed estrogen stimulation to endometrium.
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PMID:[Recent progress in epidemiologic research of uterine cancer]. 1124 42

Suicide gene therapy using viral transfer of herpes simplex virus type I (HSV-1) thymidine kinase (TK) and subsequent ganciclovir (GCV) chemotherapy was the first approach used in clinical trials of somatic gene therapy for glioblastoma. The molecular pathways mediating TK/GCV-induced cell death remain to be elucidated. Here, we report that adenoviral (Ad)-TK/GCV-induced death is p53-independent and does not involve altered CD95 or CD95L expression. Ectopic expression of the preferential caspase 8 inhibitor, crm-A, inhibits Ad-CD95L-induced cell death but has no effect on TK/GCV cytotoxicity. LN-18 glioma cells selected for resistance to death receptor-mediated cell death do not acquire cross-resistance to TK/GCV. TK/GCV triggers mitochondrial cytochrome c release and activation of caspases 3, 7, 8 and 9 in a death receptor-independent manner. These events are associated with the loss of BCL-X(L). Forced expression of a BCL-X(L) transgene, or co-exposure to a pseudosubstrate caspase inhibitor, zVAD-fmk, inhibit TK/GCV cytotoxicity. Double-transfected cell lines expressing crm-A and enhanced green fluorescent protein (eGFP) show that the bystander effect in vitro is also death receptor- and caspase 8-independent. TK/GCV therapy does not kill glioma cells in synergy with cancer chemotherapy drugs, including lomustine, temozolomide and topotecan. In contrast, there is strong synergy of TK/GCV and CD95L. Thus, TK/GCV-induced cell death involves a mitochondria-dependent loop of caspase acvtivation that can be synergistically enhanced by death receptor agonists such as CD95L. TK/GCV-mediated sensitization of glioma cells to CD95L expressed on immune effector cells or parenchymal brain cells might account for the immune system's and bystander effects of TK/GCV therapy observed in rodent glioma models in vivo.
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PMID:Death receptor-independent cytochrome c release and caspase activation mediate thymidine kinase plus ganciclovir-mediated cytotoxicity in LN-18 and LN-229 human malignant glioma cells. 1131 26

Liver metastasis is the most serious event for physicians and surgeons treating patients with colorectal cancer. Gene therapy is expected to become a novel strategy to prevent liver metastasis. Four types of clinical studies are currently underway: 1) suicide-gene therapy with the cytosine deaminase gene; 2) immune gene therapy with cytokine (inter leukin-2) or major histocompatibility complex class I gene HLA-B7; 3) tumor suppressor gene p53 therapy; and 4) lysis of p53 mutant cancer cells with E1B55k-deleted adenovirus (Onyx-015). Basic research provided several candidates for the liver metastasis-associated genes, including MMP7, DCC, CDC25B, E-cadherin, CD44, vascular endothelial growth factor, etc. There is an alternative approach to liver metastasis, which attempts to introduce a specific gene such as cytosine deaminase and TIMP-2 into the hepatocytes but not into the tumor itself. This concept is based on results showing that hepatocytes can incorporate genes more readily than cancer cells can. Recently, mutant virus therapy has been developed, which includes Onyx-015, adenovirus dl922-947, and mutant-type herpes simplex virus. These mutant types of virus specifically proliferate in the cancer cells and result in their lysis. In the future, development of gene delivery systems that are powerful and specific to cancer type is essential.
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PMID:[Future scope for gene therapy for liver metastasis of colon cancer]. 1139 6

Promyelocytic leukemia protein (PML) bodies are nuclear sites for both input viral genome deposition and immediate-early (IE) gene transcription during infection with certain human DNA viruses, such as human cytomegalovirus (HCMV), herpes simplex virus type 1, and adenovirus. In this study, we showed that the K8 (K-bZIP) protein, an early protein encoded by the human herpesvirus 8 (HHV-8), colocalized with the PML bodies in HHV-8-infected primary effusion lymphoma cells. Cotransfection of two plasmids expressing the K8 protein and green-fluorescence protein (GFP)-PML fusion protein into 293T cells revealed that the K8 protein colocalized with PML in cells with high PML expression. Overexpression of the K8 protein in Chinese hamster ovary (CHO) cells with stable GFP-PML expression did not induce the dispersion of the PML bodies, unlike the IE1 protein of HCMV. Transfection of a truncated K8 gene revealed that the leucine zipper domain of the K8 protein was required for the colocalization with PML. We also demonstrated that the K8 protein bound to p53 in vivo and in vitro, and that high expression of the K8 protein caused the accumulation of p53 to the PML bodies in CHO cells, suggesting that the K8 protein functions in the recruitment of p53 to the PML bodies. These data suggest that the K8 protein may be associated with the functional modulation of p53 in the nucleus during the lytic phase of HHV-8.
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PMID:Human-herpesvirus-8-encoded K8 protein colocalizes with the promyelocytic leukemia protein (PML) bodies and recruits p53 to the PML bodies. 1148 12

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

The herpes simplex virus 1 (HSV-1) tegument protein VP22 has been utilised as a vehicle for trafficking proteins. It has a remarkable property of exiting the cell that is producing it and entering the neighbouring cells, which has been used to deliver therapeutic proteins, p53 and herpes simplex virus thymidine kinase (tk). It has a complex pattern of expression and subcellular localisation. Functions of VP22 include intercellular transport, binding to and bundling of microfilaments, inducing cytoskeleton collapse, nuclear translocation during mitosis, and binding to chromatin and nuclear membrane. The regions of VP22 which contain each of these functions have not been characterised. Finding the region carrying the property of intercellular spread would facilitate enhancement of transport function. By constructing a series of deletion constructs of VP22 tagged by the green fluorescent protein (GFP) we have mapped the functions of VP22 to specific regions in the polypeptide as follows: intercellular transport - aa 81-195; binding and reorganisation of cytoskeleton - aa 159-267; nuclear targeting, inhibition of cytoskeleton collapse - aa 81-121; and nuclear targeting and facilitation of intercellular transport - aa 267-301. Separation of VP22 functions enables focus on the mechanism of VP22-mediated transport and improve the transportation efficiency of VP22.
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PMID:Mapping of herpes simplex virus-1 VP22 functional domains for inter- and subcellular protein targeting. 1152 52


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