miR-16 Targets Transcriptional Corepressor SMRT and Modulates NF-kappaB-Regulated Transactivation of Interleukin-8 Gene

The signaling pathways associated with the Toll-like receptors (TLRs) and nuclear factor-kappaB (NF-κB) are essential to pro-inflammatory cytokine and chemokine expression, as well as initiating innate epithelial immune responses. The TLR/NF-κB signaling pathways must be stringently controlled through an intricate network of positive and negative regulatory elements. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the stability and/or translation of protein-coding mRNAs. Herein we report that miR-16 promotes NF-κB-regulated transactivation of the IL-8 gene by suppression of the silencing mediator for retinoid and thyroid hormone receptor (SMRT). LPS stimulation activated miR-16 gene transcription in human monocytes (U937) and biliary epithelial cells (H69) through MAPK-dependent mechanisms. Transfection of cells with the miR-16 precursor promoted LPS-induced production of IL-8, IL-6, and IL-1α, without a significant effect on their RNA stability. Instead, an increase in NF-κB-regulated transactivation of the IL-8 gene was confirmed in cells following transfection of miR-16 precursor. Importantly, miR-16 targeted the 3′-untranslated region of SMRT and caused translational suppression of SMRT. LPS decreased SMRT expression via upregulation of miR-16. Moreover, functional manipulation of SMRT altered NF-κB-regulated transactivation of LPS-induced IL-8 expression. These data suggest that miR-16 targets SMRT and modulates NF-κB-regulated transactivation of the IL-8 gene

Nuclear receptor corepressors

The ability of NR LBDs to transfer repression function to a heterologous DNA binding domain, and the cross-squelching of repression by untethered LBDs, has suggested that repression is mediated by interactions with putative cellular corepressor proteins. The yeast-two hybrid screen for protein interactors has proven to be the key to the isolation and characterization of corepressors. This short review will focus on N-CoR and SMRT

Characterization of a Low Affinity Thyroid Hormone Receptor Binding Site within the Rat GLUT4 Gene Promoter

Previous studies have demonstrated that thyroid hormone (T3) stimulates insulin-responsive glucose transporter (GLUT4) transcription and protein expression in rat skeletal muscle. The aim of the present study was to define a putative thyroid hormone response element (TRE) within the rat GLUT4 promoter and thus perhaps determine whether T3 acts directly to augment skeletal muscle GLUT4 transcription. To this end, electrophoretic mobility shift analyses were performed to analyze thyroid hormone receptor (TR) binding to a previously characterized 281-bp T3-responsive region of the rat GLUT4 promoter. Indeed, within this region, a TR-binding site of the standard DR+4 TRE variety was located between bases −457/−426 and was shown to posses a specific affinity for in vitro translated TRs. Interestingly, however, the GLUT4 TR-binding site demonstrated a significantly lower affinity compared to a consensus DR+4 TRE, and only bound TRs appreciatively in the form of high affinity heterodimers, in this case with the cis-retinoic acid receptor. In conclusion, these data demonstrated the presence of a specific TR-binding site within a T3-responsive region of the rat GLUT4 promoter and thus support the supposition that thyroid hormone acts directly to stimulate GLUT4 transcription in rat skeletal muscle. Moreover, characterization of a novel TR-binding site with low affinity suggests an additional mechanism by which the intrinsic activity and responsiveness of thyroid hormone regulated genes may be modulated

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging

The Corepressor NCoR1 Antagonizes PGC-1α and Estrogen-Related Receptor α in the Regulation of Skeletal Muscle Function and Oxidative Metabolism

Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO(2peak)), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARβ/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases

How do patients from eastern and western Germany compare with regard to their preferences for shared decision making?

Item does not contain fulltextBACKGROUND: Increasing emphasis is being placed on involving patients in decisions concerning their health. This shift towards more patient engagement by health professionals and towards more desire by patients for participation may be partly based on socio-political factors. METHODS: To compare the preferences for shared decision making of patients from eastern and western Germany we analysed five patient samples (n = 2318) (general practice patients and schizophrenia patients from eastern and western Germany). Patients' role preferences for shared decisions were measured using the decision-making subscale of the Autonomy Preference Index. RESULTS: Patients resident in eastern Germany expressed lower preferences for shared decision making than patients in western Germany. This was true after controlling for socio-demographic variables and for patient group. CONCLUSION: The cultural imprint (e.g. western vs. former communist society) seems to have a significant influence on patients' expectations and behaviour in the medical encounter. Health services providers need to be aware that health attitudes within the same health system might vary for historical and cultural reasons. The engagement of patients in medical decisions might not be susceptible to a 'one size fits all' approach; doctors should instead aim to accommodate the individual patient's desire for autonomy.1 augustus 201