Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genes encoding chemokine receptor-like proteins have been found in herpes and poxviruses and implicated in viral pathogenesis. Here we describe the cellular distribution and trafficking of a human cytomegalovirus (HCMV) chemokine receptor encoded by the US28 gene, after transient and stable expression in transfected HeLa and Cos cells. Immunofluorescence staining indicated that this viral protein accumulated intracellularly in vesicular structures in the perinuclear region of the cell and showed overlap with markers for endocytic organelles. By immunogold electron microscopy US28 was seen mostly to localize to multivesicular endosomes. A minor portion of the protein (at most 20%) was also expressed at the cell surface. Antibody-feeding experiments indicated that cell surface US28 undergoes constitutive ligand-independent endocytosis. Biochemical analysis with the use of iodinated ligands showed that US28 was rapidly internalized. The high-affinity ligand of US28, the CX(3)C-chemokine fractalkine, reduced the steady-state levels of US28 at the cell surface, apparently by inhibiting the recycling of internalized receptor. Endocytosis and cycling of HCMV US28 could play a role in the sequestration of host chemokines, thereby modulating antiviral immune responses. In addition, the distribution of US28 mainly on endosomal membranes may allow it to be incorporated into the viral envelope during HCMV assembly.
Mol Biol Cell 2001 Jun
PMID:The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. 1140 81

A number of molecular forms of DNA polymerases have been reported to be involved in eukaryotic nuclear DNA replication, with contributions from alpha-, delta-, and epsilon-polymerases. It has been reported that delta-polymerase possessed a central role in DNA replication in archaea, whose ancestry are thought to be closely related to the ancestor of eukaryotes. Indeed, in vitro experiment shown here suggests that delta-polymerase has the potential ability to start DNA synthesis immediately after RNA primer synthesis. Therefore, the question arises, where did the alpha-polymerase come from? Phylogenetic analysis based on the nucleotide sequence of several conserved regions reveals that two poxviruses, vaccinia and variola viruses, have polymerases similar to eukaryotic alpha-polymerase rather than delta-polymerase, while adenovirus, herpes family viruses, and archaeotes have eukaryotic delta-like polymerases, suggesting that the eukaryotic alpha-polymerase gene is derived from a poxvirus-like organism, which had some eukaryote-like characteristics. Furthermore, the poxvirus's proliferation independent from the host-cell nucleus suggests the possibility that this virus could infect non-nucleated cells, such as ancestral eukaryotes. I wish to propose here a new hypothesis for the origin of the eukaryotic nucleus, posing symbiotic contact of an orthopoxvirus ancestor with an archaebacterium, whose genome already had a delta-like polymerase gene.
J Mol Evol 2001 May
PMID:Poxviruses and the origin of the eukaryotic nucleus. 1144 45

Cardiotrophin-1 (CT-1) is an interleukin-6 family cytokine with known protective and hypertrophic effects in the heart. Previous studies have shown that CT-1 treatment increases heat shock protein 70 (hsp70) and heat shock protein 90 (hsp90) levels in cardiac cells. Due to the known protective effects of hsp90 and hsp70, induction of these proteins may be involved in the protective effects of CT-1. We show here that heat shock protein 56 (hsp56), also known as FK506 binding protein 59 (FKBP59), is induced by CT-1 treatment at both the mRNA and protein levels. It has been demonstrated previously that, unlike hsp70 and hsp90, hsp56 overexpression does not protect cardiac myocytes against stressful stimuli. The other known effect of CT-1 is hypertrophy, an increase in cell size without cell division, which occurs in many cardiac pathologies. We investigated the role of hsp56 in the hypertrophic response of primary neonatal rat cardiac myocytes, using overexpression with transiently transfected plasmid vectors and Herpes viral vectors. Overexpression of hsp56 caused a significant increase in cardiac cell size and protein:DNA ratio. Hsp27, hsp70 and hsp90 overexpression had no effect on cell size. An antisense construct to hsp56 reduced hsp56 levels when transiently transfected and blocked the hypertrophic effect of CT-1. This is the first time that a hypertrophic effect has been demonstrated for a heat shock protein and demonstrates that CT-1-induced hypertrophy involves a specific hsp, which is not involved in its protective effect.
J Mol Cell Cardiol 2001 Jun
PMID:Heat shock protein-56 is induced by cardiotrophin-1 and mediates its hypertrophic effect. 1144 24

We report two cases of fulminant viral myocarditis in previously healthy children. They were caused by herpes simplex virus (HSV)-1 (in a boy aged 3 years) and Epstein-Barr virus (EBV) (in a boy aged 12 months). We obtained the diagnosis of HSV-1 myocarditis by immunohistochemistry and the diagnosis of EBV myocarditis by in situ hybridization. Histologic examination of heart tissue from the two boys revealed mononuclear cell infiltration of the myocardium. Immunohistochemical staining identified these cells as CD8+ T-lymphocytes. CD8+ T-lymphocytes induced by herpes virus infections may play an important role in the damage to heart muscle fibers seen in fulminant myocarditis in previously healthy children. To our knowledge, this is the first report of HSV-1 or EBV myocarditis (at least in children) in which viral infection has been demonstrated in the myocardium.
Pediatr Pathol Mol Med
PMID:CD8+ T-lymphocytes infiltrate the myocardium in fulminant herpes virus myocarditis. 1148 49

Here we investigate the effect of morphine on herpes simplex virus-1 (HSV-1) pathogenesis using a murine flank scarification model. Murine flank scarification with HSV-1 results in primary lesions at the site of inoculation within three days and lesions at secondary sites within four days. The lesions are scored based on lesion size. Applying 0.1 mM morphine to the skin one-day post inoculation tested the effect of morphine on the formation of the herpes lesion. On days three through five, mice treated with morphine developed lesions with scores half of that observed in untreated animals, however, skin viral titers on these days were equivalent. Further, 1.0 microM morphine did not effect the replication rate of HSV-1 in Vero cells. Taken together, these data suggest the morphine reduced HSV-1 pathogenesis by modifying the host response to HSV-1 infection and not by reducing viral replication rates.
Int J Mol Med 2001 Sep
PMID:Morphine reduces herpes simplex virus-1 pathogenesis in the murine flank. 1149 59

Animal studies have shown that direct injection of an adenoviral vector (Adv.RSV-tk) expressing the herpes thymidine kinase gene into established tumors in the liver, followed by systemic ganciclovir administration, was effective in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I trial in patients with metastatic colorectal adenocarcinoma in the liver to assess the safety of intratumoral Adv.RSV-tk injection (escalating doses) followed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous needle placement with concurrent ultrasonographic monitoring to prevent injection or leakage into adjacent normal liver structures. We treated 16 patients in five dose level cohorts of Adv.RSV-tk, from 1.0x10(10) to 1.0x10(13) virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients. These results indicate that Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases at doses up to 1.0x10(13) virus particles per patient, and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.
Mol Ther 2001 Sep
PMID:Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial. 1154 8

There are two promising herpes viral-based anticancer strategies: one involves replication-defective viruses to transfer therapeutic transgenes, and the other involves replication-conditional oncolytic viruses, which selectively infect and destroy cancer cells directly. This study examines a novel dual herpesvirus preparation, which combines the immunostimulatory effects of amplicon-mediated IL2 expression with direct viral-induced oncolysis. The oncolytic virus G207 was used as the helper virus to package a herpes simplex virus (HSV)-amplicon vector carrying the gene IL2 (HSV-IL2), yielding a single preparation with two complementary modes of action. In vivo comparison was carried out in a syngeneic squamous cell carcinoma flank tumor model. We directly injected established tumors with HSV-IL2, G207, G207 mixed with HSV-IL2, or G207-packaged HSV-amplicon carrying the IL2 transgene (G207[IL2]). Significant inhibition of tumor growth was seen at 2 weeks in the G207[IL2]-treated tumors relative to controls (0.57+/-0.44 cm(3) versus 39.45+/-5.13 cm(3), P<0.00001), HSV-IL2 (20.97+/-4.60 cm(3)), and the G207 group (7.71+/-2.10 cm(3)). This unique use of a replication-conditional, oncolytic virus to package a replication-incompetent amplicon vector demonstrates impressive efficacy in vitro and in vivo, and avoids the theoretical concerns of recombination with reversion to wild type.
Mol Ther 2001 Sep
PMID:A novel approach to cancer therapy using an oncolytic herpes virus to package amplicons containing cytokine genes. 1154 16

Two general strategies are being developed to engineer mammalian artificial chromosomes (MACs) as therapeutic vectors: (i) in vitro MAC cloning by enzymatic ligation of the individual MAC components followed by propagation in single cell organisms such as bacteria or yeast; and (ii) in situ MAC assembly by co-introduction of the various MAC elements into an 'incubator' mammalian tissue culture cell and use of it as a 'foster parental' donor cell. Because of their organizational compactness, in vitro built MACs are stuitable for somatic-based human gene therapy. In contrast, the long-term persistence of in situ built MACs can be capitalized on to generate husbandry transgenic animals expressing therapeutic genes. While current MAC systems generally rely on cis-elements exclusively from viral or genomic origin, the next generation of MACs may combine both into chimeric systems. As illustration of the genetic flexibility and technological potential of chimeric MACs, the herpes viral oriP/EBNA1 system, paradigm of a self-replicating and self-segregating episome in human cells is discussed in terms of future therapeutic applications.
Curr Opin Mol Ther 1999 Apr
PMID:Therapeutic mammalian artificial episomal chromosomes. 1171 44

Herpes vector has been widely used for experimental gene therapy. We herein review the strategies of such therapy for the treatment of urologic neoplasms. Most experimental studies of genetically altered viruses have employed replication-incompetent vectors. However, such viruses are unable to infect additional cells subsequent to the initial infection event. Therefore, this strategy has relied heavily on the bystander effect because a large number of noninfected tumor cells remain. Conditionally replicating herpes vector G207 has been developed in order to overcome potential problems of safety and tumor specificity for human use. It has been used to treat malignant brain tumors because of its neural tropism. In the last few years, applications of G207 for non-neural tumors have been reported. Because G207 may be useful for the treatment of urologic malignant tumors, we evaluated the antitumor effect against several types of tumor cells both in vitro and in vivo. Our data suggest that G207 may be applicable for the treatment of urologic malignant tumors.
Mol Urol 2000
PMID:Application of conditionally replicating herpes vector for gene therapy treatment of urologic neoplasms. 1200 47

The potential for a bioterrorism-induced smallpox outbreak has been much discussed of late. The literature of the late 1960s stressed that the distinction between smallpox and the other viral-induced vesicle-forming diseases, namely varicella zoster and disseminated herpes simplex, was difficult to make. Given that the cutaneous manifestations of smallpox would be among the initial symptoms, we reviewed 2 cases of smallpox diagnosed in South America in the 1970s in conjunction with 9 cases of multiple skin vesicles diagnosed as either disseminated herpes simplex or varicella-zoster. These were examined by routine hematoxylin and eosin stain (H&E) as well as by in situ hybridization. A blind review of the cases demonstrated that each showed striking intraepithelial vesicles containing multinucleated squamous cells exhibiting a ground glass appearance of the nuclear chromatin. Thus, as expected, routine H&E examination could not differentiate the 2 smallpox cases from the other 9 samples. In situ hybridization easily distinguished the 2 cases of smallpox from the other 9 samples, 5 of which contained varicella-zoster (two had been misdiagnosed as herpes) and the other 4 were disseminated herpes simplex. The in situ test, readily accomplished in any histology-based molecular laboratory in 4 hours, allows for the rapid and specific identification of smallpox infection and, importantly, its distinction from its mimics. Formalin fixation, which is optimal for in situ hybridization, guarantees the inactivation of the smallpox virus.
Diagn Mol Pathol 2003 Jun
PMID:Rapid diagnosis of smallpox infection and differentiation from its mimics. 1276 15


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