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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gamma interferon-inducible protein 10 (IP10) is a member of the CXC family of chemokines. By differential mRNA display, we have demonstrated the upregulation of IP10 in coxsackievirus B3 (CVB3)-infected mouse hearts. Functional characterization of the IP10 gene in IP10-transfected Tet-On HeLa cells has found that IP10 induced cell apoptosis and inhibited viral replication. In the characterization of the IP10-induced apoptotic pathway, we found that overexpression of IP10 upregulated p53 and resulted in altered expression of p53-responsive genes such as the p21Cip1, p27kip1, NF-kappaB, Bax, and PUMA genes and the mitochondrial translocation of Bax. However, transduction of the IP10 cells with adenovirus expressing dominant negative p53 not only ablated p53-triggered gene expression but also abolished IP10-induced apoptosis and restored CVB3 replication to the control levels. These data suggest a novel mechanism by which IP10 inhibits viral replication through the induction of host cell death via a p53-mediated apoptotic pathway. We also found that constantly high-level expression of p53 in these tumor cells is attributed to the IP10-induced suppression of human papillomavirus E6 and E7 oncogene expression. Taken together, these data reveal not only a previously unrecognized link between chemokine IP10 and p53 in antiviral defense but also a mechanism by which IP10 inhibits tumor cell growth.
Mol Cell Biol 2005 Jul
PMID:Gamma interferon-inducible protein 10 induces HeLa cell apoptosis through a p53-dependent pathway initiated by suppression of human papillomavirus type 18 E6 and E7 expression. 1598 33

The purpose of this study was to analyze the placental and neonatal tissues in fatal cases for a wide variety of infectious agents and cytokine expression. Placentas and corresponding neonatal tissues in 21 consecutive cases of idiopathic spontaneous abortion or perinatal death, before or within 2 days of birth, were tested for an infectious agent. The controls included 10 consecutive cases of fetal and placental tissues from therapeutic abortions, 5 placentas from unremarkable childbirths, and 11 placentas from cases of spontaneous abortion or perinatal death of known cause (ruptured uterus, placenta abruption, prolapsed cord). An intrauterine infection was noted in 16 of 21 (76%) of the placentas associated with neonatal mortality; in each case, the same infectious agent was found in the neonatal tissues, primarily the spleen. The most common infectious agent was enterovirus/coxsackie virus (10 cases); the histologic findings in the placenta were nonspecific. There was strong expression of TNF-alpha in the placenta and spleen of each of the cases of intrauterine infection and in none of the 26 controls. It is concluded that in utero infection and the associated cytokine up-regulation are responsible for many cases of unexplained fetal and neonatal loss.
Diagn Mol Pathol 2005 Sep
PMID:Histologic, infectious, and molecular correlates of idiopathic spontaneous abortion and perinatal mortality. 1610 96

Stem cells, including embryonic stem (ES) cells, mesenchymal stem cells (MSCs), and hematopoietic stem cells (HSCs), are defined by their capacity for self-renewal and multilineage differentiation. Efficient gene transfer into stem cells is essential for the basic research in developmental biology and for therapeutic applications in gene-modified regenerative medicine. Adenovirus (Ad) vectors, based on Ad type 5, can efficiently and transiently introduce the exogenous gene into many cell types via the primary receptor, coxsackievirus, and adenovirus receptor (CAR). However, some kinds of stem cells, such as MSCs and HSCs, cannot be efficiently transduced with conventional Ad vectors based on Ad serotype 5 (Ad5), because of the lack of CAR expression. To overcome this problem, fiber-modified Ad vectors and an Ad vector based on another serotype of Ad have been developed. Here, we review the advances in the development of Ad vectors suitable for stem cells and discuss their application in basic biology and clinical medicine.
Mol Pharm
PMID:Adenovirus vector-mediated gene transfer into stem cells. 1657 38

Positive single-stranded RNA viruses constitute a broad and prevalent group of pathogens that threaten human health and life worldwide. While effective vaccines have been developed for some, such as poliovirus and hepatitis A, others such as coxsackievirus, severe acute respiratory syndrome coronavirus (SARS-CoV) and West Nile virus have no accredited drug treatments. Antisense technologies, which encompass small interfering RNA, antisense oligonucleotides, ribozymes and their chemically modified analogs, involve small sequence-specific nucleic-acid-based molecules that inhibit viral replication at the level of translation. Many antisense oligomers are proven antiviral agents in vitro. In this review, iwe provide an overview of the antiviral antisense field, highlighting specific studies of interest over the past several years, using our experience with coxsackievirus B3 as a reference point. Overall, both the challenges and successes of existing antisense therapies for positive single-stranded RNA viruses can be paralleled to those for other virus groups, and vice versa.
Curr Opin Mol Ther 2006 Apr
PMID:Nucleic-acid-based antiviral agents against positive single-stranded RNA viruses. 1661 Jul 61

Host answers to pathogen attacks define the course of pathogenic events and decide about the fate of the host organism. Infection with coxsackievirus B3 (CVB3) can induce severe myocarditis and pancreatitis. The interplay between host factors and virus components is crucial for the fate of the infected host. As we have shown before, expression of the pro-apoptotic host protein Siva is significantly increased after CVB3 infection, and infected cells are removed by programmed cell death. Analysis of Siva expressed in Escherichia coli revealed that this protein binds three zinc ions, suggesting a rather complex three-dimensional structure. By screening a human heart cDNA library we found a new interaction partner of Siva. The peroxisomal membrane protein PMP22 may be involved in the host response against CVB3. Previous investigations showed that Siva interacts with the cytoplasmic C-terminus of CD27, a member of the tumor necrosis factor receptor group, and transmits an apoptotic signal. With the help of directed two-hybrid assays we determined the N-terminal part of Siva as the binding region for CD27.
Mol Cell Biochem 2006 Jul
PMID:The zinc containing pro-apoptotic protein siva interacts with the peroxisomal membrane protein pmp22. 1668 88

The domain V within the internal ribosome entry segment (IRES) of poliovirus (PV) is expected to be important in its own neurovirulence because it contains an attenuating mutation in each of the Sabin vaccine strains. In this study, we try to find out if the results observed in the case of Sabin vaccine strains of PV can be extrapolated to another virus belonging to the same genus of enteroviruses but with a different tropism. To test this hypothesis, we used the coxsackievirus B3 (CVB3), known to be the most common causal agent of viral myocarditis. The introduction of the three PV Sabin-like mutations in the equivalent positions (nucleotides 484, 485, and 473) to the domain V of the CVB3 IRES results in significant reduced viral titer of the Sabin3-like mutant (Sab3-like) but not on those of Sab1- and Sab2-like mutants. This low titer was correlated with poor translation efficiency in vitro when all mutants were translated in rabbit reticulocyte lysates. However, elucidation by biochemical probing of the secondary structure of the entire domain V of the IRES of Sabin-like mutants reveals no distinct profiles in comparison with the wild-type counterpart. Prediction of secondary structure by MFOLD program indicates a structural perturbation of the stem containing the Sab3-like mutation, suggesting that specific protein-viral RNA interactions are disrupted, preventing efficient viral translation.
Mol Genet Genomics 2006 Oct
PMID:Effects of the Sabin-like mutations in domain V of the internal ribosome entry segment on translational efficiency of the Coxsackievirus B3. 1690 84

Coxsackie adenovirus receptor (CAR) is involved in immunological processes, and its soluble isoforms have antiviral effects on coxsackievirus B3 (CVB3) infection in vitro. We explored in this study the impact of CAR4/7, a soluble CAR isoform, on CVB3-induced myocarditis in BALB/c mice. BALB/c mice were treated daily with recombinant CAR4/7, beta-galactosidase (beta-Gal; as control protein) or buffer for 9 days. Half of each group was infected with CVB3 on day 3, and all mice were killed on day 9. Myocardial CVB3 titer, histology, and serology were analyzed. Treatment with CAR4/7 led to a significant reduction of myocardial CVB3 titer, whereas the application of beta-Gal had no detectable effect on the myocardial virus load. CAR4/7 application, however, resulted in increased myocardial inflammation and tissue damage in CVB3-infected hearts, whereas beta-Gal caused a degree of cardiac inflammation and injury similar to that in buffer-treated CVB3-infected control animals. CAR4/7 and beta-Gal treatment induced the production of antibodies against the respective antigens. CAR4/7-, but not beta-Gal-specific, virus-negative sera reacted against myocardial tissue and cellular membranous CAR, and significantly inhibited CVB3 infection in vitro. Thus, CAR4/7 suppressed CVB3 infection in vivo, supporting the concept of receptor analog in antiviral therapy. However, CAR4/7 treatment also leads to an aggravation of myocardial inflammation and injury most likely secondary to an autoimmune process.
J Mol Med (Berl) 2006 Oct
PMID:Treatment of coxsackievirus-B3-infected BALB/c mice with the soluble coxsackie adenovirus receptor CAR4/7 aggravates cardiac injury. 1692 71

Adenoviral vector mediated gene delivery has been applied in clinical trials and mechanistic studies to explore new treatment approaches for lung cancers. The expression of coxsackievirus adenovirus receptor (CAR), the primary receptor for the most commonly used adenovirus serotype 5 (Ad5)-based vectors, predominantly determines the permissiveness of lung cancer cells. CAR expression is also suggested to modulate tumor cell proliferation capacity. Here, we studied CAR expression in archival lung cancer specimens by using well-characterized CAR 72 antibodies. High levels of CAR expression were observed in most of the 32 cases of squamous cell carcinoma lung cancers and in all the five cases of small cell lung cancers investigated. In contrast, high levels of CAR expression were detected only in 6 of 22 adenocarcinoma lung cancers. The relative levels of CAR expression did not correlate with the pathologic grade in lung cancers, and was thus inconsistent with a role of modulating cancer cell proliferation. Of note, CAR expression was not detected in non-malignant alveolar cells. Our data suggest a preferred utility of Ad5 vector mediated gene delivery to squamous cell carcinoma lung cancers, small cell lung cancers, but not to the majority of adenocarcinoma lung cancers.
J Mol Histol 2006 May
PMID:Coxsackievirus and adenovirus receptor expression in non-malignant lung tissues and clinical lung cancers. 1703 23

The lengthy 5' nontranslated region of coxsackievirus B3 (CVB3) forms a highly ordered secondary structure containing an internal ribosome entry segment (IRES), which plays an important role in controlling viral translation and pathogenesis. The stem-loop V (SL-V) of this IRES contains a large lateral bulge loop which encompasses two conserved GNRA motifs. In this study, we analyzed the effects of point mutations within the GNRA motifs of the CVB3 IRES. We characterized in vitro virus production and translation efficiency and we tested in vivo virulence of two CVB3 mutants produced by site-directed mutagenesis. The GNAA1 and GNAA2 RNAs displayed decreased translation initiation efficiency when translated in rabbit reticulocyte lysates. This translation defect was correlated with reduced yields of infectious virus particles in HeLa cells in comparison with the wild type. When inoculated orally into Swiss mice, both mutant viruses were avirulent and caused neither inflammation nor necrosis in hearts. These results highlight the important role of the GNRA motifs within the SL-V of the IRES of CVB3, in directing translation initiation.
J Mol Microbiol Biotechnol 2008
PMID:Role of GNRA motif mutations within stem-loop V of internal ribosome entry segment in coxsackievirus B3 molecular attenuation. 1769 2

Dilated cardiomyopathy (DCM) as a consequence of viral myocarditis is a worldwide cause of morbidity and death. The deposition of matrix proteins, such as collagen, in the course of ongoing viral myocarditis results in cardiac remodeling and finally in cardiac fibrosis, the hallmark of DCM. To identify mediators of virus-induced cardiac fibrosis, microarray analysis was conducted in a murine model of chronic coxsackievirus B3 (CVB3) myocarditis. By this attempt, we identified connective tissue growth factor (CTGF) as a novel factor highly expressed in infected hearts. Further investigations by quantitative reverse transcription polymerase chain reaction and Western blot analysis confirmed a strong induction of cardiac CTGF expression in the course of CVB3 myocarditis. By in situ hybridization and immunohistochemistry, basal CTGF messenger ribonucleic acid (mRNA) and protein expression were confined in noninfected control hearts mainly to endothelial cells, whereas in CVB3-infected hearts, also numerous fibroblasts were found to express CTGF. Regulation of CTGF is known to be basically mediated by transforming growth factor (TGF)-beta. In the course of CVB3 myocarditis, CTGF upregulation coincided with increased cardiac TGF-beta and procollagen type I mRNA expression, preceding the formation of fibrotic lesions. In in vitro experiments, we found that downregulation of CVB3 replication by means of small interfering RNAs (siRNAs) reverses the upregulation of CTGF mRNA expression. In contrast, downregulation of CTGF by siRNA molecules did not significantly reduce viral load, indicating that CTGF is not essential for CVB3 life cycle. The significantly enhanced transcript levels of TGF-beta, CTGF, and procollagen type I in cultivated CVB3-infected primary cardiac fibroblasts substantiate the role of fibroblasts as a relevant cell population in cardiac remodeling processes. We conclude that CTGF is a crucial molecule in the development of fibrosis in ongoing enteroviral myocarditis. Thus, downregulation of cardiac CTGF expression may open novel therapeutic approaches counteracting the development of cardiac fibrosis and subsequent heart muscle dysfunction.
J Mol Med (Berl) 2008 Jan
PMID:Connective tissue growth factor: a crucial cytokine-mediating cardiac fibrosis in ongoing enterovirus myocarditis. 1808 Jan 5


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