Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins

Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFβ-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFβ. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-κB family member RELB. We show that RELB represses TGFβ target promoters independently of DNA binding at NF-κB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFβ gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth

The Online Shadow of Offline Signals: Which Sellers Get Contacted in Online B2B Marketplaces?

This article extends the understanding of what impels buyers to contact particular sellers in online business-to-business (B2B) marketplaces, which are typically characterized by sparse social structures and concomitant limitations in observing social cues. Integrating an institutional perspective with signaling theory, our core argument is that offline seller characteristics that are visible online—in particular, geographic location and legal status—convey credible signals of seller behavior because they provide buyers with information on sellers’ local institutional quality and the institutionally-induced obligations and controls acting on sellers. Using unique data from a large Italian online B2B marketplace between the fourth quarter of 1999 and July 2001, we find that both sellers’ local institutional quality and their legal statuses affect a buyer’s likelihood of contacting a seller. Moreover, consistent with the idea that a buyer’s own local institutional quality generates a relevant reference point against which sellers are evaluated, we find that a buyer is progressively more likely to contact sellers the higher their local institutional quality relative to the buyer. Jointly, our findings imply that in online B2B marketplaces, signals conveyed by sellers’ geographic locations and legal statuses may constitute substantive sources of competitive heterogeneity and market segmentation

Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models.

Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases

EQ-5D in Central and Eastern Europe : 2000-2015

Objective: Cost per quality-adjusted life year data are required for reimbursement decisions in many Central and Eastern European (CEE) countries. EQ-5D is by far the most commonly used instrument to generate utility values in CEE. This study aims to systematically review the literature on EQ-5D from eight CEE countries. Methods: An electronic database search was performed up to July 1, 2015 to identify original EQ-5D studies from the countries of interest. We analysed the use of EQ-5D with respect to clinical areas, methodological rigor, population norms and value sets. Results: We identified 143 studies providing 152 country-specific results with a total sample size of 81,619: Austria (n=11), Bulgaria (n=6), Czech Republic (n=18), Hungary (n=47), Poland (n=51), Romania (n=2), Slovakia (n=3) and Slovenia (n=14). Cardiovascular (20%), neurologic (16%), musculoskeletal (15%) and endocrine/nutritional/metabolic diseases (14%) were the most frequently studied clinical areas. Overall 112 (78%) of the studies reported EQ VAS results and 86 (60%) EQ-5D index scores, of which 27 (31%) did not specify the applied tariff. Hungary, Poland and Slovenia have population norms. Poland and Slovenia also have a national value set. Conclusions: Increasing use of EQ-5D is observed throughout CEE. The spread of health technology assessment activities in countries seems to be reflected in the number of EQ-5D studies. However, improvement in informed use and methodological quality of reporting is needed. In jurisdictions where no national value set is available, in order to ensure comparability we recommend to apply the most frequently used UK tariff. Regional collaboration between CEE countries should be strengthened

Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation

The apoptosis-modulating protein Daxx functions as a transcriptional repressor that binds to and suppresses the activity of nuclear factor-κB member RelB, among other transcription factors. The mechanism by which Daxx represses RelB target genes remains elusive. In this report, we demonstrate that Daxx controls epigenetic silencing of RelB target genes by DNA methylation. Daxx potently represses the RelB target genes dapk1, dapk3, c-flip, and birc3 (ciap2) at both the mRNA and protein levels. Recruitment of Daxx to target gene promoters, and its ability to repress them, is RelB-dependent, as shown by experiments using relB−/− cells. Importantly, methylation of target promoters is decreased in daxx−/− cells compared with daxx+/+ cells, and stable transfection of daxx−/− cells with Daxx restores DNA methylation. Furthermore, Daxx recruits DNA methyl transferase 1 (Dnmt1) to target promoters, resulting in synergistic repression. The observation that Daxx functions to target DNA methyltransferases onto RelB target sites in the genome provides a rare example of a gene-specific mechanism for epigenetic silencing. Given the documented role of several of the RelB-regulated genes in diseases, particularly cancer, the findings have implications for developing therapeutic strategies based on epigenetic-modifying drugs

Cross-media communication in advertising: exploring multimodal connections between television commercials and websites

The aim of this article is to advance current understandings of cross-media communication in advertising. The study is based on a sample of 80 television commercials and their announced websites, and the article is inspired by recent studies of cross-media advertising effectiveness as well as semiotic perspectives on multimodal analysis. The authors present three dimensions to be considered when examining multimodal connections between television commercials and websites: announcements, participants and address strategy. These dimensions are brought together in an analytical framework that can serve as inspiration for further research on cross-media communication in advertising and possibly in other types of communication