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David J. Hughes Jennifer J. Wood Brian R. Jackson Belinda Baquero-Pérez Adrian Whitehouse 《PLoS pathogens》2015,11(3)
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi''s sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies. 相似文献
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Kaposi sarcoma-associated herpesvirus (KSHV),also known as human herpesvirus 8 (HHV-8),is discovered in 1994 from Kaposi's sarcoma (KS) lesion of an acquired immunodeficiency syndrome (AIDS)patient.In addition to its association with KS,KSHV has also been implicated as the causative agent of two other AIDS-associated malignancies:primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD).KSHV is a complex DNA virus that not only has the ability to promote cellular growth and survival for tumor development,but also can provoke deregulated angiogenesis,inflammation,and modulate the patient's immune system in favor of tumor growth.As KSHV is a necessary but not sufficient etiological factor for KS,human immunodeficiency virus (HIV) is a very important cofactor.Here we review the basic information about the biology of KSHV,development of pathogenesis and interaction between KSHV and HIV. 相似文献
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Sabine M. Lang Meisha O. F. Bynoe Roshan Karki Michael A. Tartell Robert E. Means 《PloS one》2013,8(2)
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of multicentric Castleman’s disease, primary effusion lymphoma and Kaposi’s sarcoma. In this study, we show that like the C-type lectin DC-SIGN, the closely related DC-SIGNR can also enhance KSHV infection. Following infection, they are both targeted for down modulation and our data indicate that the KSHV MARCH-family ubiquitin ligase K5 is mediating this regulation and subsequent targeting for degradation of DC-SIGN and DC-SIGNR in the context of the virus. The closely related viral K3 protein, is also able to target these lectins in exogenous expressions studies, but only weakly during viral infection. In addition to requiring a functional RING-CH domain, several protein trafficking motifs in the C-terminal region of both K3 and K5 are important in regulation of DC-SIGN and DC-SIGNR. Further exploration of this modulation revealed that DC-SIGN is endocytosed from the cell surface in THP-1 monocytes, but degraded from an internal location with minimal endocytosis in HEK-293 cells. Pull-down data indicate that both K3 and K5 preferentially associate with immature forms of the lectins, mediating their ubiquitylation and degradation. Together, these data emphasize the molecular complexities of K3 and K5, while expanding the repertoire of targets of these two viral proteins. 相似文献
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Hong Seok Choi Vaibhav Jain Brian Krueger Vickie Marshall Chang Hee Kim Joanna L. Shisler Denise Whitby Rolf Renne 《PLoS pathogens》2015,11(11)
KSHV is a DNA tumor virus that causes Kaposi’s sarcoma. Upon KSHV infection, only a limited number of latent genes are expressed. We know that KSHV infection regulates host gene expression, and hypothesized that latent genes also modulate the expression of host miRNAs. Aberrant miRNA expression contributes to the development of many types of cancer. Array-based miRNA profiling revealed that all six miRNAs of the oncogenic miR-17-92 cluster are up-regulated in KSHV infected endothelial cells. Among candidate KSHV latent genes, we found that vFLIP and vCyclin were shown to activate the miR-17-92 promoter, using luciferase assay and western blot analysis. The miR-17-92 cluster was previously shown to target TGF-β signaling. We demonstrate that vFLIP and vCyclin induce the expression of the miR-17-92 cluster to strongly inhibit the TGF-β signaling pathway by down-regulating SMAD2. Moreover, TGF-β activity and SMAD2 expression were fully restored when antagomirs (inhibitors) of miR-17-92 cluster were transfected into cells expressing either vFLIP or vCyclin. In addition, we utilized viral genetics to produce vFLIP or vCyclin knock-out viruses, and studied the effects in infected TIVE cells. Infection with wildtype KSHV abolished expression of SMAD2 protein in these endothelial cells. While single-knockout mutants still showed a marked reduction in SMAD2 expression, TIVE cells infected by a double-knockout mutant virus were fully restored for SMAD2 expression, compared to non-infected TIVE cells. Expression of either vFLIP or vCycIin was sufficient to downregulate SMAD2. In summary, our data demonstrate that vFLIP and vCyclin induce the oncogenic miR-17-92 cluster in endothelial cells and thereby interfere with the TGF-β signaling pathway. Manipulation of the TGF-β pathway via host miRNAs represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS. 相似文献
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Kaposi’s sarcoma-associated herpesvirus (KSHV) is causally related to Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and a proportion of cases of multicentric Castleman’s disease (MCD). The ORF73 protein was cloned into pQE80L-orf73 and expressed in E.coli and purified. The expressed recombinant ORF73 was identified by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE). A protein of about 27 kDa was expressed as expected. Western Blotting showed that the purified recombinant ORF73 r... 相似文献
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The facial width-to-height ratio (fWHR) has been identified as a reliable predictor of men’s behavior, with researchers focusing on evolutionary selection pressures as the underlying mechanism explaining these relationships. In this paper, we complement this approach and examine the extent to which social processes also determine the extent to which men’s fWHR serves as a behavioral cue. Specifically, we propose that observers’ treatment of target men based on the targets’ fWHR subsequently affects behavior, leading the targets to behave in ways that are consistent with the observers’ expectations (i.e., a self-fulfilling prophecy). Results from four studies demonstrate that individuals behave more selfishly when interacting with men with greater fWHRs, and this selfish behavior, in turn, elicits selfish behavior in others. 相似文献
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Katrin Fink Hans-J?rg Busch Natascha Bourgeois Meike Schwarz Dennis Wolf Andreas Zirlik Karlheinz Peter Christoph Bode Constantin von zur Muhlen 《PloS one》2013,8(2)
Objective
The endothelial protein C-receptor (EPCR) is an endothelial transmembrane protein that binds protein C and activated protein C (APC) with equal affinity, thereby facilitating APC formation. APC has anticoagulant, antiapoptotic and antiinflammatory properties. Soluble EPCR, released by the endothelium, may bind activated neutrophils, thereby modulating cell adhesion. EPCR is therefore considered as a possible link between the anticoagulant properties of protein C and the inflammatory response of neutrophils. In the present study, we aimed to provide proof of concept for a direct binding of EPCR to the β2 –integrin Mac-1 on monocytic cells under static and physiological flow conditions.Measurements and Main Results
Under static conditions, human monocytes bind soluble EPCR in a concentration dependent manner, as demonstrated by flow cytometry. Binding can be inhibited by specific antibodies (anti-EPCR and anti-Mac-1). Specific binding was confirmed by a static adhesion assay, where a transfected Mac-1 expressing CHO cell line (Mac-1+ cells) bound significantly more recombinant EPCR compared to Mac-1+ cells blocked by anti-Mac-1-antibody and native CHO cells. Under physiological flow conditions, monocyte binding to the endothelium could be significantly blocked by both, anti-EPCR and anti-Mac-1 antibodies in a dynamic adhesion assay at physiological flow conditions. Pre-treatment of endothelial cells with APC (drotrecogin alfa) diminished monocyte adhesion significantly in a comparable extent to anti-EPCR.Conclusions
In the present study, we demonstrate a direct binding of Mac-1 on monocytes to the endothelial protein C receptor under static and flow conditions. This binding suggests a link between the protein C anticoagulant pathway and inflammation at the endothelium side, such as in acute vascular inflammation or septicaemia. 相似文献14.
Roth J Yam GH Fan J Hirano K Gaplovska-Kysela K Le Fourn V Guhl B Santimaria R Torossi T Ziak M Zuber C 《Histochemistry and cell biology》2008,129(2):163-177
In cells the quality of newly synthesized proteins is monitored in regard to proper folding and correct assembly in the early
secretory pathway, the cytosol and the nucleoplasm. Proteins recognized as non-native in the ER will be removed and degraded
by a process termed ERAD. ERAD of aberrant proteins is accompanied by various changes of cellular organelles and results in
protein folding diseases. This review focuses on how the immunocytochemical labeling and electron microscopic analyses have
helped to disclose the in situ subcellular distribution pattern of some of the key machinery proteins of the cellular protein
quality control, the organelle changes due to the presence of misfolded proteins, and the efficiency of synthetic chaperones
to rescue disease-causing trafficking defects of aberrant proteins. 相似文献
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Bieberich E 《Neurochemical research》2012,37(6):1208-1229
Lipids are often considered membrane components whose function is to embed proteins into cell membranes. In the last two decades,
studies on brain lipids have unequivocally demonstrated that many lipids have critical cell signaling functions; they are
called “bioactive lipids”. Pioneering work in Dr. Robert Ledeen’s laboratory has shown that two bioactive brain sphingolipids,
sphingomyelin and the ganglioside GM1 are major signaling lipids in the nuclear envelope. In addition to derivatives of the
sphingolipid ceramide, the bioactive lipids discussed here belong to the classes of terpenoids and steroids, eicosanoids,
and lysophospholipids. These lipids act mainly through two mechanisms: (1) direct interaction between the bioactive lipid
and a specific protein binding partner such as a lipid receptor, protein kinase or phosphatase, ion exchanger, or other cell
signaling protein; and (2) formation of lipid microdomains or rafts that regulate the activity of a group of raft-associated
cell signaling proteins. In recent years, a third mechanism has emerged, which invokes lipid second messengers as a regulator
for the energy and redox balance of differentiating neural stem cells (NSCs). Interestingly, developmental niches such as
the stem cell niche for adult NSC differentiation may also be metabolic compartments that respond to a distinct combination
of bioactive lipids. The biological function of these lipids as regulators of NSC differentiation will be reviewed and their
application in stem cell therapy discussed. 相似文献
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Vorob'eva O. V. Vasil'ev S. A. Karyagina A. S. Oretskaya T. S. Kubareva E. A. 《Molecular Biology》2000,34(6):921-926
Heterocyclic bases and phosphate groups involved in the DNA–methyltransferase SsoII (M·SsoII) interaction were identified in the regulatory DNA region localized within the promoter region of the SsoII restriction–modification genes by footprinting with the use of formic acid, hydrazine, dimethyl sulfate, and N-ethyl-N-nitrosourea as modifying agents. It has been established that the enzyme interacts with three guanines, one adenine, two thymines, and three phosphate groups of each strand of the DNA duplex. These heterocyclic bases and phosphate groups are disposed symmetrically within the 15-mer inverted repeat of the regulatory DNA region. It has been demonstrated by footprinting with dimethyl sulfate that the C7 atoms of guanines interacting with the enzyme are exposed to the DNA major groove. Two theoretical models were built describing the contacts in a complex between M·SsoII and the regulatory DNA region. 相似文献
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Feng Zhou Min Xue Di Qin Xiaofei Zhu Cong Wang Jianzhong Zhu Tingting Hao Lin Cheng Xiuying Chen Zhiqiang Bai Ninghan Feng Shou-Jiang Gao Chun Lu 《PloS one》2013,8(1)
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is etiologically associated with KS, the most common AIDS-related malignancy. KS is characterized by vast angiogenesis and hyperproliferative spindle cells. We have previously reported that HIV-1 Tat can trigger KSHV reactivation and accelerate Kaposin A-induced tumorigenesis. Here, we explored Tat promotion of KSHV vIL-6-induced angiogenesis and tumorigenesis. Tat promotes vIL-6-induced cell proliferation, cellular transformation, vascular tube formation and VEGF production in culture. Tat enhances vIL-6-induced angiogenesis and tumorigenesis of fibroblasts and human endothelial cells in a chicken chorioallantoic membrane (CAM) model. In an allograft model, Tat promotes vIL-6-induced tumorigenesis and expression of CD31, CD34, SMA, VEGF, b-FGF, and cyclin D1. Mechanistic studies indicated Tat activates PI3K and AKT, and inactivates PTEN and GSK-3β in vIL-6 expressing cells. , a specific inhibitor of PI3K, effectively impaired Tat’s promotion of vIL-6-induced tumorigenesis. Together, these results provide the first evidence that Tat might contribute to KS pathogenesis by synergizing with vIL-6, and identify PI3K/AKT pathway as a potential therapeutic target in AIDS-related KS patients. LY294002相似文献
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Higher brain regions are more susceptible to global ischemia than the brainstem, but is there a gradual increase in vulnerability in the caudal-rostral direction or is there a discrete boundary? We examined the interface between `higher` thalamus and the hypothalamus the using live brain slices where variation in blood flow is not a factor. Whole-cell current clamp recording of 18 thalamic neurons in response to 10 min O2/glucose deprivation (OGD) revealed a rapid anoxic depolarization (AD) from which thalamic neurons do not recover. Newly acquired neurons could not be patched following AD, confirming significant regional thalamic injury. Coinciding with AD, light transmittance (LT) imaging during whole-cell recording showed an elevated LT front that initiated in midline thalamus and that propagated into adjacent hypothalamus. However, hypothalamic neurons patched in paraventricular nucleus (PVN, n= 8 magnocellular and 12 parvocellular neurons) and suprachiasmatic nucleus (SCN, n= 18) only slowly depolarized as AD passed through these regions. And with return to control aCSF, hypothalamic neurons repolarized and recovered their input resistance and action potential amplitude. Moreover, newly acquired hypothalamic neurons could be readily patched following exposure to OGD, with resting parameters similar to neurons not previously exposed to OGD. Thalamic susceptibility and hypothalamic resilience were also observed following ouabain exposure which blocks the Na+/K+ pump, evoking depolarization similar to OGD in all neuronal types tested. Finally, brief exposure to elevated [K+]o caused spreading depression (SD, a milder, AD-like event) only in thalamic neurons so SD generation is regionally correlated with strong AD. Therefore the thalamus-hypothalamus interface represents a discrete boundary where neuronal vulnerability to ischemia is high in thalamus (like more rostral neocortex, striatum, hippocampus). In contrast hypothalamic neurons are comparatively resistant, generating weaker and recoverable anoxic depolarization similar to brainstem neurons, possibly the result of a Na/K pump that better functions during ischemia. 相似文献
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Kuan Hua Khor Tyson A. Moore Ian A. Shiels Ristan M. Greer Thiruma V. Arumugam Paul C. Mills 《PloS one》2016,11(1)