Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization.

The human innate immune system recognizes dsRNA as a pathogen-associated molecular pattern that induces a potent inflammatory response. The primary source of pathogenic dsRNA is cells infected with replicating viruses, but can also be released from uninfected necrotic cells. Here, we show that the dsRNA poly(I:C) challenge in human macrophages activates the p38 MAPK-MK2 signalling pathway and subsequently the phosphorylation of tristetraprolin (TTP/ZFP36).

Global analysis of the abundance of AU-rich mRNAs in response to glucocorticoid treatment.

Glucocorticoids (GC) like dexamethasone (Dex) are potent anti-inflammatory agents with diverse cellular functions including the potentiation of the activity of AU-rich elements (AREs). AREs are cis-acting instability sequence elements located in the 3'UTRs of many inflammatory mediator mRNAs. Here, available RNA-seq data were used to investigate the effect of GCs on the ARE-mRNA-transcriptome.

Post-transcriptional regulation of BIRC5/survivin expression and induction of apoptosis in breast cancer cells by tristetraprolin.

Inhibition of apoptosis is one of the hallmarks of cancer and is a target of various therapeutic interventions. BIRC5 is an inhibitor of apoptosis that is aberrantly expressed in cancer leading to sustained growth of tumours. Post-transcriptional control mechanisms involving RNA-binding proteins and AU-rich elements (AREs) are fundamental to many cellular processes and changes in the expression or function of these proteins can promote an aberrant and pathological phenotype.

Wild-type S100A3 and S100A13 restore calcium homeostasis and mitigate mitochondrial dysregulation in pulmonary fibrosis patient-derived cells.

Patients with digenic S100A3 and S100A13 mutations exhibited an atypical and progressive interstitial pulmonary fibrosis, with impaired intracellular calcium homeostasis and mitochondrial dysfunction. Here we provide direct evidence of a causative effect of the mutation on receptor mediated calcium signaling and calcium store responses in control cells transfected with mutant S100A3 and mutant S100A13. We demonstrate that the mutations lead to increased mitochondrial mass and hyperpolarization, both of which were reversed by transfecting patient-derived cells with the wild type S100A3 and S100A13, or extracellular treatment with the recombinant proteins.

β-catenin attenuation leads to up-regulation of activating NKG2D ligands and tumor regression in -driven thyroid cancer cells.

Introduction: mutations frequently occur in papillary thyroid cancer (PTC). β-catenin, encoded by , is a key downstream component of the canonical Wnt signaling pathway and is often overexpressed in PTC. -driven PTC tumors rely on Wnt/β-catenin signaling to sustain growth and progression.

Differential upregulation of AU-rich element-containing mRNAs in COVID-19.

Background: AU-rich elements (AREs) are located in the 3'UTRs of 22% of human mRNAs, including most transiently expressed inflammatory mediators. By default, AREs mark mRNAs for decay and translational inhibition, but this activity can be temporarily inhibited in case of infection to allow the onset of inflammation. Morbidity and mortality in COVID-19 patients have been associated with dysregulated inflammation, a process that may include aberrant ARE activity.

Post-transcriptional screen of cancer amplified genes identifies ERBB2/Her2 signaling as AU-rich mRNA stability-promoting pathway.

Amplification of specific cancer genes leads to their over-expression contributing to tumor growth, spread, and drug resistance. Little is known about the ability of these amplified oncogenes to augment the expression of cancer genes through post-transcriptional control. The AU-rich elements (ARE)-mediated mRNA decay is compromised for many key cancer genes leading to their increased abundance and effects.

β-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAF-Driven Thyroid Cancer Animal Model.

mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin () is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. -driven tumors have been speculated to rely on Wnt/β-catenin signaling to sustain its growth, although many details remain to be elucidated.

Kinome inhibition reveals a role for polo-like kinase 1 in targeting post-transcriptional control in cancer.

Dysfunctions in post-transcriptional control are observed in cancer and chronic inflammatory diseases. Here, we employed a kinome inhibitor library (n = 378) in a reporter system selective for 3'-untranslated region-AU-rich elements (ARE). Fifteen inhibitors reduced the ARE-reporter activity; among the targets is the polo-like kinase 1 (PLK1).

Clinical and functional significance of tumor/stromal ATR expression in breast cancer patients.

Background: Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis. Therefore, we investigated here the role of the protein kinase ATR in breast stromal fibroblasts in the prognosis of locally advanced breast cancer patients.

Methods: We have used immunohistochemistry to assess the level of ATR in breast cancer tissues and their adjacent normal tissues.

Post-Transcriptional Inflammatory Response to Intracellular Bacterial c-di-AMP.

Cyclic-di-AMP (c-di-AMP) is a bacterial second messenger that is produced by intracellular bacterial pathogens in mammalian host macrophages. Previous reports have shown that c-di-AMP is recognized by intracellular pattern recognition receptors of the innate immune system and stimulate type I interferon response. Here we report that the response to c-di-AMP includes a post-transcriptional component that is involved in the induction of additional inflammatory cytokines including IL-6, CXCL2, CCL3, and CCL4.

An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes and .

Background: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death.

Methods: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated.

Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels.

AU-rich elements (AREs) are cis-acting instability and translation inhibition elements that are present in the 3'UTR of most inducible inflammatory mRNAs such as TNF and Cxcl2. mRNAs that contain AREs are, by default, repressed and only transiently expressed in response to stimuli. They are targeted by the inducible RNA-binding protein Tristetraprolin (TTP) which blocks their translation and facilitates their decay, thereby contributing to the quick termination of their expression.

The intracellular pyrimidine 5'-nucleotidase NT5C3A is a negative epigenetic factor in interferon and cytokine signaling.

The enzyme pyrimidine 5'-nucleotidase (NT5C3A), which mediates nucleotide catabolism, was previously thought to be restricted to blood cells. We showed that expression of the gene encoding NT5C3A was induced by type I interferons (IFNs) in multiple cell types and that NT5C3A suppressed cytokine production through inhibition of the nuclear factor κB (NF-κB) pathway. expression required both an intronic IFN-stimulated response element and the IFN-stimulated transcription factor IRF1.

The AU-rich element landscape across human transcriptome reveals a large proportion in introns and regulation by ELAVL1/HuR.

Adenylate-uridylate (AU)-rich elements (AREs) are sequence instability elements that are known to be located in the 3' untranslated regions (UTR) in thousands of human transcripts. AREs regulate the expression of many genes at the post-transcriptional level, and they are essential for many normal cellular functions. We conducted a transcriptome-wide screen for AREs and found that they are most abundant in introns, with up to 25% of introns containing AREs corresponding to 58% of human genes.

Identification of a novel genetic locus underlying tremor and dystonia.

Background: Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes.

ARED-Plus: an updated and expanded database of AU-rich element-containing mRNAs and pre-mRNAs.

Here we present an updated version of the AU-Rich Element Database (ARED-Plus) that is freely available at http://brp.kfshrc.edu.

Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas.

Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC.

Hallmarks of cancer and AU-rich elements.

Post-transcriptional control of gene expression is aberrant in cancer cells. Sustained stabilization and enhanced translation of specific mRNAs are features of tumor cells. AU-rich elements (AREs), cis-acting mRNA decay determinants, play a major role in the posttranscriptional regulation of many genes involved in cancer processes.

Systematic Analysis of AU-Rich Element Expression in Cancer Reveals Common Functional Clusters Regulated by Key RNA-Binding Proteins.

Defects in AU-rich elements (ARE)-mediated posttranscriptional control can lead to several abnormal processes that underlie carcinogenesis. Here, we performed a systematic analysis of ARE-mRNA expression across multiple cancer types. First, the ARE database (ARED) was intersected with The Cancer Genome Atlas databases and others.

Human Cytokinome Analysis for Interferon Response.

Unlabelled: Cytokines are a group of small secreted proteins that mediate a diverse range of immune and nonimmune responses to inflammatory and microbial stimuli. Only a few of these cytokines mount an antiviral response, including type I, II, and III interferons (IFNs). During viral infections and under inflammatory conditions, a number of cytokines and chemokines are coproduced with IFN; however, no systematic study exists on the interactions of the cytokine repertoire with the IFN response.

Posttranscriptional control of the chemokine receptor CXCR4 expression in cancer cells.

CXCR4 is a chemokine receptor that is overexpressed in certain cancer types and involved in migration toward distant organs. The molecular mechanisms underlying CXCR4 expression in invasive cancer, particularly posttranscriptional regulation, are poorly understood. Here, we find that CXCR4 harbors AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR) that bind and respond to the RNA-binding proteins, tristetraprolin (TTP/ZFP36) and HuR (ELAVL1).