47 research outputs found

    Antiviral activity of the mineralocorticoid receptor NR3C2 against Herpes simplex virus Type 1 (HSV-1) infection

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    Abstract Analysis of a genome-scale RNA interference screen of host factors affecting herpes simplex virus type 1 (HSV-1) revealed that the mineralocorticoid receptor (MR) inhibits HSV-1 replication. As a ligand-activated transcription factor the MR regulates sodium transport and blood pressure in the kidney in response to aldosterone, but roles have recently been elucidated for the MR in other cellular processes. Here, we show that the MR and other members of the mineralocorticoid signalling pathway including HSP90 and FKBP4, possess anti-viral activity against HSV-1 independent of their effect on sodium transport, as shown by sodium channel inhibitors. Expression of the MR is upregulated upon infection in an interferon (IFN) and viral transcriptional activator VP16-dependent fashion. Furthermore, the MR and VP16, together with the cellular co-activator Oct-1, transactivate the hormone response element (HRE) present in the MR promoter and those of its transcriptional targets. As the MR induces IFN expression, our data suggests the MR is involved in a positive feedback loop that controls HSV-1 infection

    TBP Binding-Induced Folding of the Glucocorticoid Receptor AF1 Domain Facilitates Its Interaction with Steroid Receptor Coactivator-1

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    The precise mechanism by which glucocorticoid receptor (GR) regulates the transcription of its target genes is largely unknown. This is, in part, due to the lack of structural and functional information about GR's N-terminal activation function domain, AF1. Like many steroid hormone receptors (SHRs), the GR AF1 exists in an intrinsically disordered (ID) conformation or an ensemble of conformers that collectively appears to be unstructured. The GR AF1 is known to recruit several coregulatory proteins, including those from the basal transcriptional machinery, e.g., TATA box binding protein (TBP) that forms the basis for the multiprotein transcription initiation complex. However, the precise mechanism of this process is unknown. We have earlier shown that conditional folding of the GR AF1 is the key for its interactions with critical coactivator proteins. We hypothesize that binding of TBP to AF1 results in the structural rearrangement of the ID AF1 domain such that its surfaces become easily accessible for interaction with other coactivators. To test this hypothesis, we determined whether TBP binding-induced structure formation in the GR AF1 facilitates its interaction with steroid receptor coactivator-1 (SRC-1), a critical coactivator that is important for GR-mediated transcriptional activity. Our data show that stoichiometric binding of TBP induces significantly higher helical content at the expense of random coil configuration in the GR AF1. Further, we found that this induced AF1 conformation facilitates its interaction with SRC-1, and subsequent AF1-mediated transcriptional activity. Our results may provide a potential mechanism through which GR and by large other SHRs may regulate the expression of the GR-target genes

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

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    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

    Design and synthesis of a C-2-symmetric self-complementary hydrogen-bonding cleft molecule based on the bicyclo 3.3.1 nonane and 4-oxo-5-azaindole framework. Formation of channels and inclusion complexes in the solid state

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    The synthesis of a C-2-symmetric cleft molecule 2 based on the fused framework between bicyclo-[3.3. 1] nonane and 4-oxo-5-azaindole, incorporating a self-complementary hydrogen-bonding motif, in both racemic and enantiomerically pure forms is reported. This cleft molecule is reminiscent of analogues of Troger's base though with different cleft dimensions and tilt angles. The framework of 2 provides a building block for the construction of self-assembled hydrogen-bonded supramolecular structures. The solid-state structure of 2 is highly influenced by the limited solubility of (+/-)-2 and (-)-2. The solvents interact with the potential hydrogen-bonding motifs of (+/-)-2 and (-)-2, forming different three-dimensional structures as revealed by X-ray diffraction analysis. In the solid state (+/-)-(2)(2)(.)5DMF forms hydrogen-bonded pleated band structures that build up three-dimensional pens between adjacent bands in which two molecules of DMF are trapped. In contrast, the aggregate obtained from (-)-2, (-)-2(.)2AcOH, showed infinite bands of complex constitution

    Quantification and clinical relevance of gene amplification at chromosome 17q12-q21 in human epidermal growth factor receptor 2-amplified breast cancers.

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    International audienceIntroduction: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers represent a tumor subtype with chromosome 17q rearrangements that lead to frequent gene amplifications. The aim of this study was to quantify the amplification of genes located on chromosome 17q and to analyze the relations between the pattern of gene amplifications and the patients' characteristics and survival.Methods: Patients with HER2-positive breast tumors (HER2 score of 3+ by immunohistochemistry or positive for HER2 amplification by fluorescence in situ hybridization (FISH)) (n = 86) and with HER2-negative breast tumors (n = 40) (negative controls) were included in this study. Using a quantitative polymerase chain reaction method and DNA extracted from frozen tumor specimens, 11 genes (MED1, STARD3, HER2, GRB7, THRA, RARA, TOP2A, IGFBP4, CCR7, KRT20, KRT19 and GAS), which are localized within Chr17q12-q21 and have a putative role in breast cancer development, were quantified. Relapse-free and overall survival rates were estimated from the date of surgery to the date of the event of interest (recurrence or death) using the Kaplan-Meier method.Results: Gene amplification was observed only in HER2-positive tumors, and the frequency of amplification decreased with the distance of the gene from HER2. HER2 presented the highest level of amplification. TOP2A was not included in the smallest region of amplification involving HER2. Amplification of RARA, KRT20 and KRT19 was significantly associated with node-positive breast cancer (P = 0.030, P = 0.002 and P = 0.033, respectively). During a median follow-up period of 55 months (range, 6 to 81 months), the subgroup of patients with hormone receptor-negative cancer and without TOP2A amplification showed the worst survival (relapse-free survival: hazard ratio (HR) = 0.29, 95% confidence interval (95% CI), 0.13 to 0.65, P = 0.001; and overall survival: HR = 0.28, 95% CI, 0.10 to 0.76, P = 0.008).HER2 amplification seems to drive genomic instability along chromosome 17q, leading to different patterns of gene amplification. This study confirms the clinical importance of identifying, among patients with HER2-positive breast tumors, the subgroup of patients with hormone receptor-negative and nonamplified TOP2A cancers as they have the worst prognosis

    Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns

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    Because of the concern about environmental chemicals with oestrogenic and anti-oestrogenic effects, there is a need to construct biosensors for classifying such chemicals according to their effect on oestrogen receptor conformation. The conformation of the ligand-binding domains (LBD) of oestrogen receptor-alpha and -beta determine their transcription regulation activity. Some ligands, i.e., the natural oestrogen oestradiol, induce an active conformation allowing interaction with co-activators. In contrast, antagonists like ICI 182, 780, because of their bulky side chains, do not allow an alpha-helix 12 positioning compatible with co-activator binding. Another type of oestrogen receptor-ligand interactions, termed "passive antagonism", was first defined by X-ray crystal structure analysis of receptors in complex with the side chain-less 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC). We have now used the ability of peptides selected from phage-displayed peptide libraries to bind conformation specifically to oestrogen receptor-alpha and -beta LBDs to analyse conformations induced by THC and a group of chlorinated biphenyls and their aryl-hydroxylated metabolites, suspected of being environmental chemical disruptors. In oestrogen receptor-P, THC defined a "passive antagonist" peptide recognition pattern, which was also induced by several antagonistic hydroxylated biphenyls, while a clearly different peptide recognition pattern was induced by their chlorinated agonistic counterparts. In oestrogen receptor-alpha, THC induced a conformation similar to that induced by oestriol and other oestrogen receptor-alpha agonists, which, as evaluated by site-directed mutagenesis, have a functionally important interaction with oestrogen receptor-a residue His524. We conclude that the peptide recognition pattern can be used to classify suspected environmental endocrine disruptors according the oestrogen receptor-alpha and -beta conformations they induce
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