Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key regulator of the activation of transcription factor NF-κB by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR)... Show moreTumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key regulator of the activation of transcription factor NF-κB by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily. Recruitment of TRAF6 to the receptor-associated IRAK1-IRAK4-MyD88 adaptor protein complex induces lysine 63 (K63) autopolyubiquitination of TRAF6, which leads to further recruitment of downstream regulators, such as TAB2/3 and TAK1, and subsequently triggers NF-κB activation. Here, we identified the putative E2 ubiquitin-conjugating (UBC) enzyme UBE2O as a novel negative regulator of TRAF6-dependent NF-κB signaling. We found that UBE2O binds to TRAF6 to inhibit its K63-polyubiquitination, and to prevent the activation of NF-κB by IL-1β and lipopolysaccharides (LPS). We further show that the inhibitory effect of UBE2O is independent of its carboxy-terminal UBC domain. In contrast, we found that UBE2O acts to disrupt the IL-1β-induced association of TRAF6 with MyD88. These results provide novel insight into the regulation of signaling by IL-1R/TLR and TRAF6.Cell Research advance online publication 5 February 2013; doi:10.1038/cr.2013.21. Show less
Zhang, J.; Zhang, X.F.; Zhang, L.; Zhou, F.F.; Dinther, M. van; Dijke, P. ten 2012
The canonical Wnt pathway plays an important role in the regulation of cell proliferation and differentiation. Activation of this signaling pathway causes disruption of the Axin/adenomatous... Show moreThe canonical Wnt pathway plays an important role in the regulation of cell proliferation and differentiation. Activation of this signaling pathway causes disruption of the Axin/adenomatous polyposis coli/glycogen synthase kinase 3 beta complex, resulting in stabilization of beta-catenin and its association with lymphoid enhancer factor/T-cell factor in the nucleus. Here, we identify Fas-associated factor 1 (FAF1) as a negative regulator of Wnt/beta-catenin signaling. We found overexpression of FAF1 to strongly inhibit Wnt-induced transcriptional reporter activity and to counteract Wnt-induced beta-catenin accumulation. Moreover, knockdown of FAF1 resulted in an increase in beta-catenin levels and in activation of Wnt/beta-catenin-induced transcription. FAF1 was found to interact with beta-catenin upon inhibition of proteasome. Ectopic expression of FAF1 promoted beta-catenin degradation by enhancing its polyubiquitination. Functional studies in C2C12 myoblasts and KS483 preosteoblastic cells showed that FAF1 depletion resulted in activation of endogenous Wnt-induced genes and enhanced osteoblast differentiation, whereas FAF1 overexpression had the opposite effect. These results identify FAF1 as a novel inhibitory factor of canonical Wnt signaling pathway. Show less
Canelas, A.B.; Harrison, N.; Fazio, A.; Zhang, J.; Pitkanen, J.-P.; Brink, J. van den; ... ; Nielsen, J. 2010
Background: Based on extensive mitochondrial DNA (mtDNA) sequence data, we previously showed that the model of speciation among species of herring gull (Larus argentatus) complex was not that of a... Show moreBackground: Based on extensive mitochondrial DNA (mtDNA) sequence data, we previously showed that the model of speciation among species of herring gull (Larus argentatus) complex was not that of a ring species, but most likely due more complex speciation scenario's. We also found that two species, herring gull and glaucous gull (L. hyperboreus) displayed an unexpected biphyletic distribution of their mtDNA haplotypes. It was evident that mtDNA sequence data alone were far from sufficient to obtain a more accurate and detailed insight into the demographic processes that underlie speciation of this complex, and that extensive autosomal genetic analysis was warranted. Results: For this reason, the present study focuses on the reconstruction of the phylogeographic history of a limited number of gull species by means of a combined approach of mtDNA sequence data and 230 autosomal amplified fragment length polymorphism (AFLP) loci. At the species level, the mtDNA and AFLP genetic data were largely congruent. Not only for argentatus and hyperboreus, but also among a third species, great black-backed gull (L. marinus) we observed two distinct groups of mtDNA sequence haplotypes. Based on the AFLP data we were also able to detect distinct genetic subgroups among the various argentatus, hyperboreus, and marinus populations, supporting our initial hypothesis that complex demographic scenario's underlie speciation in the herring gull complex. Conclusions: We present evidence that for each of these three biphyletic gull species, extensive mtDNA introgression could have taken place among the various geographically distinct subpopulations, or even among current species. Moreover, based on a large number of autosomal AFLP loci, we found evidence for distinct and complex demographic scenario's for each of the three species we studied. A more refined insight into the exact phylogeographic history within the herring gull complex is still impossible, and requires detailed autosomal sequence information, a topic of our future studies. Show less
Objective. To examine the association between baseline bone mineral density (BMD) and radiographic damage at 3 years of disease duration in a longitudinal cohort of African Americans with recent... Show moreObjective. To examine the association between baseline bone mineral density (BMD) and radiographic damage at 3 years of disease duration in a longitudinal cohort of African Americans with recent-onset rheumatoid arthritis (RA). Methods. African American RA patients with a disease duration of <2 years (n = 141) were included in the study. All patients underwent baseline BMD measurements (femoral neck and/or lumbar spine) using dual x-ray absorptiometry. T scores were calculated using normative data from the general population of African Americans. Patients were categorized as having osteopenia/osteoporosis (T score less than or equal to -1) or as being healthy. Hand and wrist radiographs, obtained at baseline and at 3 years of disease duration, were scored using the modified Sharp/van der Heijde method. The association between baseline BMD and total radiographic score at 3 years of disease was examined using multivariable negative binomial regression. Results. At baseline, the mean age and the mean disease duration were 52.4 years and 14.8 months, respectively; 85.1% of the patients were women. The average total radiographic scores at baseline and at 3 years of disease were 2.4 and 5.7, respectively. In the final reduced multivariable model, adjusting for age, sex, anti-cyclic citrullinated peptide antibody positivity, and the presence of radiographic damage at baseline, the total radiographic score at 3 years disease in patients with osteopenia/osteoporosis of the femoral neck was twice that in patients with normal bone density, and the difference was statistically significant (P = 0.0084). No association between lumbar spine osteopenia/osteoporosis and radiographic score was found. Conclusion. Our findings suggest that reduced generalized BMD may be a predictor of future radiographic damage and support the hypothesis that radiographic damage and reduced generalized BMD in RA patients may share a common pathogenic mechanism. Show less
Kleine-Vehn, J.; Huang, F.; Naramoto, J.; Zhang, J.; Offringa, R.; Michniewicz, M.; Friml, J. 2009
This thesis presents a thorough survey of the central aspects of the phonology of Shaoxing Chinese from a synchronic perspective and on the basis of recent theoretical phonological developments,... Show moreThis thesis presents a thorough survey of the central aspects of the phonology of Shaoxing Chinese from a synchronic perspective and on the basis of recent theoretical phonological developments, with the secondary goal of casting some light on current issues in Modern Chinese (Mandarin). In particular, the thesis presents an analysis of syllable structure, focusing on the syllabic status of the prenuclear glide in Shaoxing, contributing a multiple-specifier X-bar syllable structure, which allows a syllable to be parsed into Onset and Final, instead of Onset and Rhyme. It argues that the prenuclear glide in Shaoxing is neither in the Onset nor in the Rhyme, but located in the specifier position of N''. This thesis claims that both voiced initial obstruents and low-register tones, though in complementary distribution, occur in the underlying representation in Shaoxing. It assumes that there are 'filler' onsets in the surface representation to satisfy the consonant-tone correlation and that there are also onsetless syllables which are toneless when unstressed, enabling liaison in Chinese. The thesis also presents a systematic and explicit formulation of the intricacies of tone sandhi in SX. It assumes that tone sandhi in Shaoxing is realized by tone feature spreading and delinking, and does not involve register features. It presents a metrically-based analysis with a hierarchical constraint ranking that precisely captures the tonal sandhi behaviour and accounts for all the sandhi rules in Shaoxing disyllabic structures. Show less
