Dengue virus (DV) is a flavivirus and infects mammalian cells through mosquito vectors. This study investigates the roles of domain III of DV type 2 envelope protein (EIII) in DV bindingDengue virus (DV) is an arthropod-borne human pathogen that causes a serious public health threat in tropical and subtropical regions of the world (58). The World Health Organization reports that there are approximately 500,000 cases of dengue fever per year and that the infection rate is approximately 50 million per year (see reference 15 and literature cited therein). DV has four serotypes (DEN-1 to DEN-4) that cause diseases ranging from mild dengue fever to severe symptoms such as dengue hemorrhagic fever and dengue shock syndrome (17,25,27,70).The dengue viral genome is a single-stranded, positivestrand RNA with genome organization similar to those of other flaviviruses (47). DV infects a broad range of mammalian cell lines from several species in vitro but is transmitted to humans in vivo by mosquito vectors such as Aedes aegypti and Aedes albopictus (7). Primary human cells such as peripheral blood leukocytes, blood monocytes/macrophages, dendritic cells, and B lymphocytes could also be infected by DV (9,12,13,28,32,33,46,53,55,75,76,82).Previous studies indicate that cell surface heparan sulfates (HS) are involved in attachment of DV to mammalian cells including Vero, CHO, and human hepatoma cells (11,23,31,35,44,54). HS are repeating disaccharides composed of uronic acid or L-iduronic acid and a derivative of glucosamine that is variably O-sulfated (21). Extensive sulfate modification causes cell surface HS to be highly negatively charged. The biological roles of HS are quite diverse, including cell attachment and migration, compressive resilience of cartilage, control of fibrinogenesis, cell signaling, and virus infection (3). Many pathogenic microorganisms, including viruses, gram-positive and gram-negative bacteria, and parasites, attach to HS during entry into host cells (14,69,74). Since HS is ubiquitously expressed on many cell types and is commonly used by other pathogens to gain access into cells, an additional coreceptor has been postulated to explain the limited cell tropism of DV. This coreceptor may be related to a trypsin-sensitive protein or protein complex that was shown to play a role in virion binding to mammalian cells (18,52). Several candidate coreceptor proteins for DV have been suggested for many mammalian cell lines. These proteins are between 20 to 40 kDa and 60 to 90 kDa in size and bind to dengue virions in vitro (5,31,56,59,66). Recently, DC-SIGN, a dendritic cell surface lectin, was shown to mediate DV infection to primary dendritic cells (61,81). Nevertheless, the molecular mechanism by which DV enters these cells remains poorly characterized.Besides mammalian cells, mosquito cell lines that express cell surface proteins capable of binding to DV were also reported. In C6/36 cells, 40-to 45-kDa cell surface proteins were identified to bind 83). Additional candidate coreceptors on C6/36 cells w...

Protein ubiquitination is an important mechanism for regulating the activity and levels of proteins under physiological conditions. Loss of regulation by protein ubiquitination leads to various diseases, such as cancer. Two types of enzymes, namely, E1/E2/E3 ligases and deubiquitinases, are responsible for controlling protein ubiquitination. The ubiquitin-specific peptidases (USPs) are the main members of the deubiquitinase family. Many studies have addressed the roles of USPs in various diseases. An increasing number of studies have indicated that USPs are critical for cancer progression, and some USPs have been used as targets to develop inhibitors for cancer prevention. Herein we collect and organize most of the recent studies on the roles of USPs in cancer progression and discuss the development of USP inhibitors for cancer therapy in the future.

We have previously demonstrated that USP24 is involved in cancer progression. Here, we found that USP24 expression is upregulated in M2 macrophages and lung cancer cells. Conditioned medium from USP24-knockdown M2 macrophages decreases the migratory and chemotactic activity of lung cancer cells and the angiogenic properties of human microvascular endothelial cell 1 (HMEC-1). IL-6 expression is significantly decreased in USP24-knockdown M2 macrophages and lung cancer cells, and IL-6-replenished conditioned medium restores the migratory, chemotactic and angiogenetic properties of the cells. USP24 stabilizes p300 and β-TrCP to increase the levels of histone-3 acetylation and NF-κB, and decreases the levels of DNMT1 and IκB, thereby increasing IL-6 transcription in M2 macrophages and lung cancer cells, results in cancer malignancy finally. IL-6 has previously been a target for cancer drug development. Here, we provide direct evidence to support that USP24 promotes IL-6 expression, which might be beneficial for cancer therapy.

Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem-like cell (CSC) marker in human cancers; however, the specific ALDH1-regulated function and its underlying signalling pathways have not been fully demonstrated. Here, we investigated the ALDH1-regulated function and its underlying signalling and tested whether all-trans retinoic acid (ATRA) can suppress ALDH1-regulated tumour behaviour in ovarian cancer cells. By modulating ALDH1 expression using flow cytometry enrichment and exogenous overexpression or knockdown, we showed that the ALDH1 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model. The findings indicate that the ALDH1 directly regulates the functions of ovarian cancer cells. We also showed that ALDH1 can regulate the expression of FoxM1 and Notch 1, which are involved in the downstream signalling of ALDH1-mediated biofunctions. Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells. ATRA reduced ALDH1 expression, suppressed tumour formation and inhibited sphere formation, cell migration and invasion in ALDH1-abundant ovarian cancer cells. We conclude that ATRA downregulates ALDH1/FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells.

Vaccinia virus does not grow in Chinese hamster ovary (CHO-K1) cells in the absence of a viral host range factor, cowpox protein CP77. In this study, CP77 was fused to the C terminus of green fluorescence protein (GFP-CP77) and a series of nested deletion mutants of GFP-CP77 was constructed for insertion into a vaccinia virus host range mutant, VV-hr, and expressed from a viral early promoter. Deletion mapping analyses demonstrated that the N-terminal 352 amino acids of CP77 were sufficient to support vaccinia virus growth in CHO-K1 cells, whereas the C-terminal residues 353 to 668 were dispensable. In yeast two-hybrid analyses, CP77 bound to a cellular protein, HMG20A, and GST pulldown analyses showed that residues 1 to 234 of CP77 were sufficient for this interaction. After VV-hr virus infection of CHO-K1 cells, HMG20A was translocated from the nucleus to viral factories and bound to the viral genome via the HMG box region. In control VV-hr-infected CHO-K1 cells, binding of HMG20A to the viral genome persisted from 2 to 8 h postinfection (h p.i.); in contrast, when CP77 was expressed, the association of HMG20A with viral genome was transient, with little HMG20A remaining bound at 8 h p.i. This indicates that dissociation of HMG20A from viral factories correlates well with CP77 host range activity in CHO-K1 cells. Finally, in cells expressing a CP77 deletion protein (amino acids 277 to 668) or a ⌬ANK5 mutant that did not support vaccinia virus growth and did not contain the HMG20A binding site, HMG20A remained bound to viral DNA, demonstrating that the binding of CP77 to HMG20A is essential for its host range function. In summary, our data revealed that a novel cellular protein, HMG20A, the dissociation of which from viral DNA is regulated by CP77, providing the first cellular target regulated by viral host range CP77 protein.