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285 records · Page 16Linked to original sources
PubMed2004

Cellular and viral requirements for rapid endocytic entry of herpes simplex virus.

It was recently demonstrated that herpes simplex virus (HSV) successfully infects Chinese hamster ovary (CHO) cells expressing glycoprotein D (gD) receptors and HeLa cells by an endocytic mechanism (A. V. Nicola, A. M. McEvoy, and S. E. Straus, J. Virol. 77:5324-5332, 2003). Here we define cellular and viral requirements of this pathway. Uptake of intact, enveloped HSV from the cell surface into endocytic vesicles was rapid (t(1/2) of 8 to 9 min) and independent of the known cell surface gD receptors. Following uptake from the surface, recovery of intracellular, infectious virions increased steadily up to 20 min postinfection (p.i.), which corresponds to accumulation of enveloped virus in intracellular compartments. There was a sharp decline in recovery by 30 min p.i., suggesting loss of the virus envelope as a result of capsid penetration from endocytic organelles into the cytosol. In the absence of gD receptors, endocytosed virions did not successfully penetrate into the cytosol but were instead transported to lysosomes for degradation. Inhibitors of phosphatidylinositol (PI) 3-kinase, such as wortmannin, blocked transport of incoming HSV to the nuclear periphery and virus-induced gene expression but had no effect on virus binding or uptake. This suggests a role for PI 3-kinase activity in trafficking of HSV through the cytosol. Viruses that lack viral glycoproteins gB, gD, or gH-gL were defective in transport to the nucleus and had reduced infectivity. Thus, similar to entry via direct penetration at the cell surface, HSV entry into cells by wortmannin-sensitive endocytosis is efficient, involves rapid cellular uptake of viral particles, and requires gB, gD, and gH-gL.

Androstadienes↗
PubMed2004

Entry of herpes simplex virus mediated by chimeric forms of nectin1 retargeted to endosomes or to lipid rafts occurs through acidic endosomes.

Herpes simplex virus (HSV) enters cells by fusion with target membranes, commonly the plasma membrane. In some cells, including CHO cells expressing the nectin1 or herpesvirus entry mediator receptors, entry occurs through an endocytic route. We report the following results. (i) When expressed in J cells, nectin1 and HVEM mediated a pathway of entry insensitive to endosome acidification inhibitors. (ii) A chimeric nectin1 receptor competent for endosomal uptake by fusion of the nectin1 ectodomain with the transmembrane sequence and cytoplasmic tail of the epidermal growth factor receptor (EGFR1) (nectin1-EGFR1) and chimeric nectin1 sorted to lipid rafts by a glycosylphosphatidylinositol anchor mediated endocytic entry blocked by the early endosome inhibitor wortmannin and by the endosome acidification inhibitors bafilomycin and NH(4)Cl. (iii) Entry mediated by nectin1-EGFR1 was selectively inhibited by AG1478, a tyrosine phosphorylation inhibitor that targets the EGFR1 cytoplasmic tail and blocks the signaling pathway that culminates in clathrin-dependent uptake of the receptor into endosomes. We draw the following conclusions. (i) The same receptor may initiate different routes of infection, depending on the cell in which it is expressed. Hence, the cell is a determinant that controls whether a given receptor initiates a plasma membrane or an endocytic route of entry. (ii) Receptors whose physiology involves uptake into endosomes or sorting to lipid rafts are suitable to serve as HSV receptors. (iii) Structural features of the receptors are additional determinants that control whether HSV entry occurs at the plasma membrane or at endosomes. These findings are relevant to studies of HSV retargeting to specific receptors.

Ammonium Chloride↗
PubMed2004

The herpes simplex virus JMP mutant enters receptor-negative J cells through a novel pathway independent of the known receptors nectin1, HveA, and nectin2.

The herpes simplex virus type 1(JMP) [HSV-1(JMP)] mutant was selected for its ability to grow and form plaques in receptor-negative J cells. It enters J cells through a novel gD-dependent pathway, independent of all known HSV receptors, nectin1, nectin2, and HveA. Evidence that the pathway is dependent on a nectin3 binding site on HSV-1(JMP) and requires three mutations in gD rests on the following. We derived monoclonal antibodies to nectin3 and show that J cells express nectin3. HSV-1(JMP) entry and cell-to-cell spread were inhibited by soluble nectin3-Fc, demonstrating that virions carry a binding site for nectin3. The site is either directly involved in HSV-1(JMP) entry, or nectin3 binding to its site affects the gD domains involved in entry (entry site). HSV-1(JMP) entry and cell-to-cell spread in J cells were also inhibited by soluble nectin1-Fc, showing that the nectin1 binding site on gD(JMP) overlaps with the entry site or that nectin1 binding to gD affects the entry site. gD(JMP) carries three mutations, S140N, R340H, and Q344R. The latter two lie in the C tail and are present in the parental HSV-1(MP). HSV-1 strain R5000 carrying the S140N substitution was not infectious in J cells, indicating that this substitution was not sufficient. We constructed two recombinants, one carrying the three substitutions and the other carrying the two C-tail substitutions. Only the first recombinant infected J cells with an efficiency similar to that of HSV-1(JMP), indicating that the three mutations are required for the novel entry pathway. The results highlight plasticity in gD which accounts for changes in receptor usage.

Animals↗
PubMed2005

A role for herpesvirus entry mediator as the receptor for herpes simplex virus 1 entry into primary human trabecular meshwork cells.

The human eye is an important target for infection with herpes simplex virus 1 (HSV-1). Damage to cells forming the trabeculum of the eye by HSV-1 infection could contribute to the development of glaucoma, a major blinding disease. Primary cultures of human trabecular meshwork cells were used as an in vitro model to demonstrate the ability of HSV-1 to enter into and establish a productive infection of the trabeculum. Blocking of entry by anti-herpesvirus entry mediator (HVEM) antibody implicated HVEM as the major receptor for HSV-1 infection.

Cell Adhesion Molecules↗
PubMed2006

Genetic evidence for the role of loci at 19q13 in cleft lip and palate.

BACKGROUND: Clefts of the lip and palate are common birth defects, affecting approximately 1 in 700 births worldwide. The aetiology of clefting is complex, with multiple genetic and environmental influences. METHODS: Genotype based linkage disequilibrium analysis was conducted using the family based association test (FBAT) and the likelihood ratio test (LRT). We also carried out direct sequencing of the PVR and PVRL2 candidate genes based on their homology to PVRL1, a gene shown previously to cause Margarita Island clefting. Participants included 434 patients with cleft lip with or without cleft palate or cleft palate only and their mothers from eight countries in South America, 205 nuclear triads (father-mother-affected child) from Iowa, 541 nuclear triads from Denmark, and 100 patients with cleft lip and palate from the Philippines. RESULTS: An allelic variant in the PVR gene showed statistically significant association with both South American and Iowa populations (p = 0.0007 and p = 0.0009, respectively). Direct sequencing of PVR and PVRL2 yielded 26 variants, including two rare amino acid changes, one in each gene, which were not seen in controls. CONCLUSIONS: We found an association between a common variant in a gene at 19q and isolated clefting in two heterogeneous populations. However, it is unclear from our data if rare variants in PVR and PVRL2 are sufficient to cause clefting in isolation.

Alleles↗
PubMed2002

The poliovirus receptor related 2 (PRR2) and apolipoprotein E genes and coronary heart disease.

BACKGROUND: Recently, we localized the Human Poliovirus Receptor Related 2 Gene (PRR2) 17kb centromeric to the gene for apolipoprotein E (APOE). Common polymorphisms in the latter have been found, in some studies, to be related to coronary heart disease (CHD) but the PRR2 gene has not been studied in this context. Here, we examined relationships between a PRR2 Sau96I (A/G) polymorphism, the epsilon2, 3 and 4 alleles of APOE and CHD. DESIGN AND METHODS: Consecutive Caucasian patients (n = 640) < 50 years with angiographically documented coronary obstructive disease and/or with unequivocal myocardial infarction were compared with 624 control subjects, aged 30-50 years, randomly selected from the community and without a history of CHD. RESULTS: An excess of PRR2-A homozygotes was observed in cases (20% vs. 15%; OR 1.4, CI 1.04-1.86, P = 0.026) particularly in those with single vessel disease (OR 1.7, CI 1.2-2.4, P <0.01). The A allele was in linkage disequilibrium with the epsilon4 allele and the G allele with the epsilon2. Overrepresentation of the A allele and underrepresentation of the G allele in the CHD group did not reach significance (P = 0.054). While the epsilon2 allele was underrepresented in the CHD group (OR 0.64, CI 0.46-0.89, P = 0.009), the epsilon4 allele was not significantly overrepresented. CONCLUSION: The relationship between the PRR2 Sau96I (A/G) polymorphism and early onset coronary artery disease may be due to linkage disequilibrium with the APOE gene and underrepresentation, or a protective effect, of the epsilon2 allele. Alternatively, since A allele homozygosity is particularly overrepresented, the relationship could be more direct, perhaps through a viral association.

Adult↗
PubMed2003

Characterization of the Prr1 response regulator with special reference to sexual development in Schizosaccharomyces pombe.

The histidine (His)-to-Aspartate (Asp) phosphorelay is a paradigm of intracellular signaling systems through protein phosphorylation in both prokaryotes and eukaryotes. The fission yeast Schizosaccharomyces pombe has three histidine kinases (Phk1/Mak2, Phk2/Mak3, and Phk3/Mak1), together with two response regulators (Mcs4 and Prr1). The results of recent extensive studies suggested that these His-to-Asp phosphorelay components are involved in oxidative stress responses through the transcriptional regulation of several scavenger genes for toxic free radicals. It was also suggested that they were somehow implicated in control of both the mitotic and meiotic cell proliferations. Among these S. pombe His-to-Asp phosphorelay components, however, the function of Prr1 is less clear. We here characterized a mutant, named prr1-D418N, specifying an altered Prr1 protein that presumably acts as a gain-of-function (or constitutive-active) mutant, with special reference to sexual development. The mutant cells showed a striking phenotype in that they underwent mating even in a nitrogen-sufficient medium, under which conditions the wild-type cells hardly did so. Furthermore, the mutant cells underwent mating very rapidly in a nitrogen-deficient medium. Under anaerobic (or micro-aerobic) growth conditions, the wild-type cells were not capable of undergoing sexual development even in a nitrogen-deficient medium. The prr1-D418N cells underwent mating efficiently under such anaerobic growth conditions. Taken these together, it was suggested that the function of Prr1 is closely linked to the well-characterized signaling pathways for induction of the sexual development, in a way that this response regulator regulates a critical step of the initiation of meiosis through activating the transcription of ste11+, mam2+, and mei2+, in S. pombe.

Amino Acid Substitution↗
PubMed2005

Cadherin-mediated cell-cell adhesion in the testis.

During spermatogenesis, the differentiating germ cells migrate across the seminiferous epithelium while maintaining close contact with the surrounding Sertoli cells via specialized actin-based adherens junctions (ectoplasmic specializations) and intermediate filament-based anchoring junctions (desmosome-like junctions). Although this migration is essential for correct completion of spermatogenesis, the mechanisms that regulate these anchoring junctions are largely unknown, and most of our knowledge of cell-cell adhesion in testis is based on earlier studies in epithelial tissues. In most epithelia, members of the cadherin superfamily play key roles in intercellular adhesion. Cadherins are calcium-dependent cell-cell adhesion molecules mediating numerous homotypic cell-cell interactions. Until recently there has been controversy about the presence and localization of cadherins in the testis, but now there is increasing evidence that various types of cadherins are expressed in this organ, which underscores their importance in testicular functions. Here, we review the expression patterns, regulatory mechanisms and possible roles of the cadherin-mediated cell-cell adhesion in the testis, and particularly during spermatogenesis. Moreover, attention is paid to additional molecular adhesion complexes in the testis, to associated signaling pathways and to cell adhesion-related innovative ways for male contraception.

Adherens Junctions↗
PubMed1998

Sequencing of 42kb of the APO E-C2 gene cluster reveals a new gene: PEREC1.

Through the sequencing of a 42kb cosmid clone we describe a new gene, designated PEREC1, located approximately 1.5kb centromeric of the human apolipoprotein (APO) E-C2 cluster. The combination of dotplot analysis, predicted coding potential and interrogation of the Expressed Sequence Tag (EST) database determined the genomic organisation of PEREC1. Sequence alignment with multiple overlapping ESTs confirmed the predicted splice sites. The predicted cDNA and amino acid sequences of PEREC1 have extensive similarity to the Caenorhabditis elegans protein, C18E9.6. Conserved structural and functional motifs have been defined by combining nucleotide and amino acid analyses to identify third base degeneracy and therefore selection at the protein level. The Poliovirus Receptor Related Protein2 gene (PRR2), previously mapped to chromosome 19q13.2 by Fluorescent In-Situ Hybridisation, has also been located approximately 17kb centromeric of APO E.

Alzheimer Disease↗
PubMed2006

DNA microarray gene expression profile of T cells with the splice variants of TCRzeta mRNA observed in systemic lupus erythematosus.

We have reported that the TCRzeta mRNA with alternatively spliced 3' UTR (zeta mRNA/as-3'-untranslated region (UTR)) and zeta mRNA lacking exon 7 (zeta mRNA/exon 7-) observed in systemic lupus erythematosus patient T cells can lead to down-regulation of both zeta and TCR/CD3 complexes. To determine whether these T cells expressing decreased zeta exhibit differential transcription patterns, we transfected retrovirus vectors containing wild-type zeta cDNA, zeta cDNA/as-3' UTR, and zeta cDNA/exon 7- into murine T cell hybridoma MA5.8 cells which lack zeta expression to construct the MA5.8 mutants WT, AS3' UTR, and EX7-, respectively. FACS analyses demonstrated reduced cell surface expression of zeta and TCR/CD3 complexes on the AS3' UTR mutant and the EX7- mutant in comparison to that on the WT mutant. Total RNA was collected after stimulating the MA5.8 mutants with anti-CD3 Ab. Reverse-transcribed cDNA was applied to the mouse cDNA microarray containing 8691 genes, and the results were confirmed by real-time PCR. The results showed that 36 genes encoding cytokines and chemokines, including IL-2, IL-15, IL-18, and TGF-beta2, were down-regulated in both the AS3' UTR mutant and the EX7- mutant. Another 16 genes were up-regulated in both, and included genes associated with membranous proteins and cell damage granules, including the genes encoding poliovirus receptor-related 2, syndecan-1, and granzyme A. Increased protein expression of these genes was confirmed by Western blot and FACS analyses. Identification of these responsive genes in T cells in which the zeta and TCR/CD3 complexes were down-regulated may help to better understand the pathogenesis of systemic lupus erythematosus.

3' Untranslated Regions↗
PubMed2004

An update on the aetiology of orofacial clefts.

OBJECTIVE: To review recent data on the aetiology of cleft lip and palate. DATA SOURCES: MEDLINE literature search (1986-2003). STUDY SELECTION: Literature and data on aetiology of cleft lip and palate using the following key words: 'cleft lip', 'cleft palate', 'aetiology', and 'genetics'. DATA EXTRACTION: Relevant information and data were reviewed by the authors. DATA SYNTHESIS: Cleft lip and palate is one of the most common types of congenital malformation. The aetiology seems complex, but genetics plays a major role. Recently several genes causing syndromic cleft lip and palate have been discovered. Three of them--namely T-box transcription factor-22 (TBX22), poliovirus receptor like-1 (PVRL1), and interferon regulatory factor-6 (IRF6)--are responsible for causing X-linked cleft palate, cleft lip/palate-ectodermal dysplasia syndrome, and Van der Woude's and popliteal pterygium syndromes, respectively; they are also implied in non-syndromic cleft lip and palate. The nature and function of these genes vary widely, illustrating high vulnerability within the craniofacial developmental pathways. The aetiological complexity of non-syndromic cleft lip and palate is also exemplified by the large number of candidate genes and loci. CONCLUSIONS: The aetiology of non-syndromic cleft lip and palate is still largely unknown, but mutations in candidate genes have already been identified in a small proportion of cases of non-syndromic cleft lip and palate. Determining the relative risk of cleft lip and palate, on the basis of genetic background and environmental influence, including smoking, alcohol use, and dietary factors, will aid in genetic counselling and the development of future preventive measures.

Alcohol Drinking↗
PubMed2006

Central genetic alterations common to all HCV-positive, HBV-positive and non-B, non-C hepatocellular carcinoma: a new approach to identify novel tumor markers.

Hepatocellular carcinoma (HCC) is a common malignancy, but the prognosis remains poor due to the lack of sensitive diagnostic markers. To gain insight into the central molecular features common to all types of HCC, and to identify novel diagnostic markers or therapeutic targets for HCC, we performed a gene expression profiling analysis using a high throughput RT-PCR system. After examining the mRNA expression of 3,072 genes in 204 (119 tumor and 85 non-tumor) liver samples, we identified differential gene expression between the HCV group (n=80), HBV group (n=19) and non-B, non-C group (n=20) with a principal component analysis and a correlation spectrum analysis. After selection of genes differentially expressed between tumor and non-tumor tissues (p<0.01) within each HCC group, a total of 51 differentially expressed genes (23 upregulated and 28 downregulated genes) were found to be common to the three HCC groups. Gene Ontology grouping analysis revealed that genes with functions related to cell proliferation or differentiation and genes encoding extracellular proteins were found to be significantly enriched in these 51 common genes. Using an atelocollagen-based cell transfection array for functional analysis of eight upregulated genes, five (CANX, FAM34A, PVRL2, LAMR1, and GBA) significantly inhibited cellular apoptosis by two independent assays. In conclusion, we identified 51 differentially expressed genes, common to all HCC types. Among these genes, there was a high incidence of anti-apoptotic activity. This combination approach with the advanced statistical methods and the bioinformatical analysis may be useful for finding novel molecular targets for diagnosis and therapy.

Apoptosis↗
PubMed1998

The human poliovirus receptor related 2 protein is a new hematopoietic/endothelial homophilic adhesion molecule.

We have recently described Poliovirus Receptor Related 2 (PRR2), a new cell surface molecule homologous to the poliovirus receptor (PVR/CD155). Both molecules are transmembrane glycoproteins belonging to the Ig superfamily (IgSF). They contain 3 Ig domains of V, C2, and C2 types in their extracellular regions that share 51% aa identity. The PRR2 gene encodes two mRNA isoforms of 3.0 kb (hPRR2 [short form]) and 4.4 kb (hPRR2delta [long form]), both widely expressed in human tissues, including hematopoietic cells. To further characterize PRR2 expression during hematopoiesis and to analyze its function, we have developed a monoclonal antibody (MoAb) directed against its extracellular region (R2.477). PRR2 was expressed in 96% of the CD34(+), 88% of the CD33(+), and 95% of the CD14(+) hematopoietic lineages and faintly in the CD41 compartment. Ectopic expression of both PRR2 cDNAs induced marked cell aggregation. A soluble chimeric receptor construct with the Fc fragment of human IgG1 (PRR2-Fc) as well as a fab fragment of the anti-PRR2 MoAb (R2.477) inhibit aggregation. PRR2-Fc binds specifically to PRR2-expressing cells. These results suggest that PRR2 is a homophilic adhesion receptor. PRR2 was also expressed at the surface of endothelial cells at the intercellular junctions of adjacent cells but not at the free cellular edges. Homophilic interactions are associated with dimerization of isoforms of PRR2 and lead to the tyrosine phosphorylation of PRR2delta. Altogether, these results suggest that homophilic properties of PRR2 could participate to the regulation of hematopoietic/endothelial cell functions.

Animals↗