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The NF-κB transcription factor has a central role in diverse processes, including inflammation, proliferation and cell survival, and its activity is dysregulated in diseases such as autoimmunity and cancer. We recently identified the TRE17/ubiquitin-specific protease 6 (USP6) oncogene as the first de-ubiquitinating enzyme to activate NF-κB. TRE17/USP6 is translocated and overexpressed in aneurysmal bone cyst (ABC), a pediatric tumor characterized by extensive bone degradation and inflammatory recruitment. In the current study, we explore the mechanism by which TRE17 induces activation of NF-κB, and find that it activates the classical NF-κB pathway through an atypical mechanism that does not involve IκB degradation. TRE17 co-precipitates with IκB kinase (IKK), and IKK activity is augmented in stable cell lines overexpressing TRE17, in a USP-dependent manner. Optimal activation of NF-κB by TRE17 requires both catalytic subunits of IKK, distinguishing its mechanism from the classical and non-canonical pathways, which require either IKKβ or IKKα, respectively. TRE17 stimulates phosphorylation of p65 at serine 536, a modification that has been associated with enhanced transcriptional activity and nuclear retention. Induction of S536 phosphorylation by TRE17 requires both IKKα and IKKβ, as well as the IKKγ/NEMO regulatory subunit of IKK. We further demonstrate that TRE17(long) is highly tumorigenic when overexpressed in NIH3T3 fibroblasts, and that inhibition of NF-κB significantly attenuates tumor formation. In summary, these studies uncover an unexpected signaling mechanism for activation of classical NF-κB by TRE17. They further reveal a critical role for NF-κB in TRE17-mediated tumorigenesis, and suggest that NF-κB inhibitors may function as effective therapeutic agents in the treatment of ABC. [ABSTRACT FROM AUTHOR]

Aneurysmal bone cyst (ABC) is an aggressive, pediatric bone tumor characterized by extensive destruction of the surrounding bone. Although first described over 60 years ago, its molecular etiology remains poorly understood. Recent work revealed that ABCs harbor translocation of TRE17/USP6, leading to its transcriptional upregulation. TRE17 encodes a ubiquitin-specific protease (USP), and a TBC domain that mediates binding to the Arf6 GTPase. However, the mechanisms by which TRE17 overexpression contributes to tumor pathogenesis, and the role of its USP and TBC domains, are unknown. ABCs are characterized by osteolysis, inflammatory recruitment and extensive vascularization, the processes in which matrix proteases have a prominent role. This led us to explore whether TRE17 regulates the production of matrix metalloproteinases (MMPs). In this study we show that TRE17 is sufficient to induce expression of MMP-9 and MMP-10, in a manner requiring its USP activity, but not its ability to bind Arf6. TRE17 induces transcription of MMP-9 through activation of nuclear factor-κB (NF-κB), mediated in part by the GTPase RhoA and its effector kinase, ROCK. Furthermore, xenograft studies show that TRE17 induces formation of tumors that reproduce multiple features of ABC, including a high degree of vascularization, with an essential role for the USP domain. In sum, these studies reveal that TRE17 is sufficient to initiate tumorigenesis, identify MMPs as novel TRE17 effectors that likely contribute to ABC pathogenesis and define the underlying signaling mechanism of their induction. [ABSTRACT FROM AUTHOR]

Background:Visfatin is an adipokine that is highly expressed in visceral fat. Plasma levels of visfatin have been reported to be higher in subjects with obesity and/or type 2 diabetes mellitus. However, the role of visfatin in endothelial dysfunction has been largely unexplored.Objectives:We investigated the possible pathogenic role of visfatin in endothelial dysfunction, particularly focusing on its effect on inflammatory mediators.Design:Primary human umbilical vein endothelial cells (HUVECs) pretreated with visfatin (1, 10 and 50 ng ml−1) were used to study the relationship between visfatin and endothelium dysfunction. Expressions of adhesion molecules (ICAM-1, VCAM-1 and E-selectin) and cytokines (interleukin (IL)-6 and IL-8) affected by visfatin were investigated by enzyme-linked immunosorbent assay, flow cytometry and real-time PCR. Activity of nuclear factor (NF)-κB was examined by electrophoretic mobility shift assay.Results:At a visfatin concentration of 50 ng ml−1, significant increases in IL-6, IL-8, ICAM-1, VCAM-1 and E-selectin gene expression along with increased IL-6, IL-8 and sE-selectin protein levels in the conditioned medium were detected. Flow cytometry showed that the addition of visfatin significantly increased ICAM-1 expression and VCAM-1 expression (10 and 50 ng ml−1, respectively). Electrophoretic mobility shift assay confirmed that visfatin increased the DNA-binding activity of NF-κB. In addition, pretreatment with visfatin (10 and 50 ng ml−1) increased human monocyte cell line THP-1 adhesion to HUVECs.Conclusions:Our findings suggest that visfatin causes endothelial dysfunction by increasing inflammatory and adhesion molecule expression at least partly through the upregulation of NF-κB activity.International Journal of Obesity (2009) 33, 465–472; doi:10.1038/ijo.2009.24; published online 17 February 2009 [ABSTRACT FROM AUTHOR]

Nausea, vomiting, and other dyspeptic symptoms are common in pregnancy. This hospital-based, cross-sectional study was designed to determine the role of Helicobacter pylori infection in gastrointestinal (GI) symptoms during pregnancy. Standardized verbal scales were used to evaluate the frequency and severity of GI symptoms in 54 women whose pregnancies were in the first 16 gestational weeks. H. pylori infection was defined as a positive serum immunoglobulin G result on an immunochromatographic assay. The H. pylori seropositivity rate was higher in the pregnant women (69%) than in the general population (approximately 50%-55%), but seropositivity did not correlate with clinical symptoms. Moreover, no specific patterns of GI symptoms were uncovered in the H. pylori-infected patients. Maternal age, body weight, parity, gestational week, and educational level were not associated with H. pylori infection; neither were the prevalence and severity of GI symptoms. [ABSTRACT FROM AUTHOR]