The RNA-binding protein PCBP1 modulates transcription by recruiting the G-quadruplex-specific helicase DHX9.

PCBP1, polycytosine (poly(C)) binding protein 1, an RNA and single-stranded DNA (ssDNA) binding protein, binds poly(C) DNA tracts but it remains unclear whether its ability to bind ssDNA contributes to transcriptional regulation. Here, we report that PCBP1's DNA binding sites are enriched at transcription start sites and that by binding to promoter regions, PCBP1 regulates transcription in addition to splicing and translation. At PCBP1 target genes, we show that PCBP1 interacts with several RNA/DNA hybrid (R-loop) associated G-quadruplex resolving helicases.

Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response.

Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3 regulatory T cells and resistance to immunotherapy.

PRMT5-mediated arginine methylation of FXR1 is essential for RNA binding in cancer cells.

Emerging evidence indicates that arginine methylation promotes the stability of arginine-glycine-rich (RGG) motif-containing RNA-binding proteins (RBPs) and regulates gene expression. Here, we report that post-translational modification of FXR1 enhances the binding with mRNAs and is involved in cancer cell growth and proliferation. Independent point mutations in arginine residues of FXR1's nuclear export signal (R386 and R388) and RGG (R453, R455 and R459) domains prevent it from binding to RNAs that form G-quadruplex (G4) RNA structures.

PCBP1 regulates LIFR through FAM3C to maintain breast cancer stem cell self-renewal and invasiveness.

The poly(rC) binding protein 1 gene (PCBP1) encodes the heterogeneous nuclear ribonucleoprotein E1 (hnRNPE1), a nucleic acid-binding protein that plays a tumor-suppressive role in the mammary epithelium by regulating phenotypic plasticity and cell fate. Following the loss of PCBP1 function, the FAM3C gene (encoding the Interleukin-like EMT inducer, or "ILEI" protein) and the leukemia inhibitory factor receptor (LIFR) gene are upregulated. Interaction between FAM3C and LIFR in the extracellular space induces phosphorylation of signal transducer and activator of transcription 3 (pSTAT3).

The ubiquitin E3 ligase ARIH1 regulates hnRNP E1 protein stability, EMT and breast cancer progression.

The epithelial to mesenchymal transition (EMT), a process that is aberrantly activated in cancer and facilitates metastasis to distant organs, requires coordinated transcriptional and post-transcriptional control of gene expression. The tumor-suppressive RNA binding protein, hnRNP-E1, regulates splicing and translation of EMT-associated transcripts and it is thought that it plays a major role in the control of epithelial cell plasticity during cancer progression. We have utilized yeast 2 hybrid screening to identify novel hnRNP-E1 interactors that play a role in regulating hnRNP-E1; this approach led to the identification of the E3 ubiquitin ligase ARIH1.

TGFβ-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis.

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial-mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo.

Heterogeneous nuclear ribonucleoprotein E1 binds polycytosine DNA and monitors genome integrity.

Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) is a tumor suppressor protein that binds site- and structure-specifically to RNA sequences to regulate mRNA stability, facilitate alternative splicing, and suppress protein translation on several metastasis-associated mRNAs. Here, we show that hnRNP E1 binds polycytosine-rich DNA tracts present throughout the genome, including those at promoters of several oncogenes and telomeres and monitors genome integrity. It binds DNA in a site- and structure-specific manner.

TGFβ promotes breast cancer stem cell self-renewal through an ILEI/LIFR signaling axis.

FAM3C/Interleukin-like EMT Inducer (ILEI) is an oncogenic member of the FAM3 cytokine family and serves essential roles in both epithelial-mesenchymal transition (EMT) and breast cancer metastasis. ILEI expression levels are regulated through a non-canonical TGFβ signaling pathway by 3'-UTR-mediated translational silencing at the mRNA level by hnRNP E1. TGFβ stimulation or silencing of hnRNP E1 increases ILEI translation and induces an EMT program that correlates with enhanced invasion and migration.

Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1).

Interleukin-like EMT inducer (ILEI, ) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell-biological process that confers metastatic properties to a tumor cell. However, very little is known about how ILEI is regulated. Here we demonstrate that ILEI is an regulator of melanoma invasiveness and is transcriptionally up-regulated by the upstream stimulatory factor-1 (USF-1), an E-box-binding, basic-helix-loop-helix family transcription factor.

TGF-beta signaling in cancer: post-transcriptional regulation of EMT via hnRNP E1.

The TGFβ signaling pathway is a critical regulator of cancer progression in part through induction of the epithelial to mesenchymal transition (EMT). This process is aberrantly activated in cancer cells, facilitating invasion of the basement membrane, survival in the circulatory system, and dissemination to distant organs. The mechanisms through which epithelial cells transition to a mesenchymal state involve coordinated transcriptional and post-transcriptional control of gene expression.

A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer.

In order to better understand the process of breast cancer metastasis, we have generated a mammary epithelial progression series of increasingly aggressive cell lines that metastasize to lung. Here we demonstrate that upregulation of an endoplasmic reticulum (ER) to Golgi trafficking gene signature in metastatic cells enhances transport kinetics, which promotes malignant progression. We observe increased ER-Golgi trafficking, an altered secretome and sensitivity to the retrograde transport inhibitor brefeldin A (BFA) in cells that metastasize to lung.

Addendum: A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression.

This corrects the article DOI: 10.1038/ncb3595.

Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma.

The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCF complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCF.

A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression.

The contribution of lncRNAs to tumour progression and the regulatory mechanisms driving their expression are areas of intense investigation. Here, we characterize the binding of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) to a nucleic acid structural element located in exon 12 of PNUTS (also known as PPP1R10) pre-RNA that regulates its alternative splicing. HnRNP E1 release from this structural element, following its silencing, nucleocytoplasmic translocation or in response to TGFβ, allows alternative splicing and generates a non-coding isoform of PNUTS.

Interleukin-like EMT inducer regulates partial phenotype switching in MITF-low melanoma cell lines.

ILEI (FAM3C) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell biological process that confers metastatic properties to a tumor cell. Initially, we found that ILEI mRNA is highly expressed in melanoma metastases but not in primary tumors, suggesting that ILEI contributes to the malignant properties of melanoma. While melanoma is not an epithelial cell-derived tumor and does not undergo a traditional EMT, melanoma undergoes a similar process known as phenotype switching in which high (micropthalmia-related transcription factor) MITF expressing (MITF-high) proliferative cells switch to a low expressing (MITF-low) invasive state.

Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling.

Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that are important for organizing membrane domains and receptor signaling and regulating the migration of effector T cells. Whether moesin plays any role during the generation of TGF-β-induced Tregs (iTregs) is unknown. Here, we have discovered that moesin is translationally regulated by TGF-β and is also required for optimal TGF-β signaling that promotes efficient development of iTregs.

PCBP1/HNRNP E1 Protects Chromosomal Integrity by Translational Regulation of CDC27.

Unlabelled: CDC27 is a core component of the anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase, whose oscillatory activity is responsible for the metaphase-to-anaphase transition and mitotic exit. Here, in normal murine mammary gland epithelial cells (NMuMG), CDC27 expression is controlled posttranscriptionally through the RNA binding protein poly(rC) binding protein 1 (PCBP1)/heterogeneous nuclear ribonucleoprotein E1 (HNRNP E1). shRNA-mediated knockdown of HNRNP E1 abrogates translational silencing of the Cdc27 transcript, resulting in constitutive expression of CDC27.

Translational regulation of inhibin βA by TGFβ via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells.

The epithelial-to-mesenchymal transition (EMT) is a cellular process that functions during embryonic development and tissue regeneration, thought to be aberrantly activated in epithelial-derived cancer and has an important role in the process of metastasis. The transforming growth factor (TGF)-β signaling pathway is a key inducer of EMT and we have elucidated a posttranscriptional mechanism by which TGFβ modulates expression of select transcripts via the RNA-binding protein hnRNP E1 during EMT. One such transcript inhibin βA is a member of the TGFβ superfamily.

Selective repression of the oncogene cyclin D1 by the tumor suppressor miR-206 in cancers.

MicroRNAs (miRNAs) are deregulated in cancer and have been shown to exhibit both oncogenic and tumor suppressive functions. Although the functional effects of several miRNAs have been elucidated, those of many remain to be discovered. In silico analysis identified microRNA-206 (miR-206) binding sites in the 3'-untranslated regions (3'-UTR) of both the mouse and human CCND1 gene.

Establishment of a TGFβ-induced post-transcriptional EMT gene signature.

A major challenge in the clinical management of human cancers is to accurately stratify patients according to risk and likelihood of a favorable response. Stratification is confounded by significant phenotypic heterogeneity in some tumor types, often without obvious criteria for subdivision. Despite intensive transcriptional array analyses, the identity and validation of cancer specific 'signature genes' remains elusive, partially because the transcriptome does not mirror the proteome.

Pulpotomy versus pulpectomy for carious vital primary incisors: randomized controlled trial.

Purpose: The purpose of this prospective, randomized, split-mouth investigation was to compare the success rates of formocresol pulpotomies (FC) and Vitapex(®) pulpectomies (RCT) in asymptomatic carious vital primary incisors.

Methods: Matched contralateral pairs of asymptomatic, carious, vital primary incisors were randomized to receive FC or RCT by 2 standardized operators and restored with stainless steel crowns. Seventy-four incisors were followed clinically and radiographically for up to 23 months.

A review of nursing workforce policies in five European countries: Denmark, Finland, Ireland, Portugal and United Kingdom*/England.

Aim: Review nursing workforce policies in five European countries: Denmark, Finland, Ireland, Portugal and the United Kingdom*.

Background: Imbalances in registered nurse (RN) supply and demand is a global, significant and recurring issue that impacts on healthcare systems, organizations, staff and patients.

Method: Policy Review using resources located by a systematic search of relevant healthcare databases and policies in Danish, English, Finnish and Portuguese over the time period 2003-2007.

Models of initial training and pathways to registration: a selective review of policy in professional regulation.

Aim: To provide a synthesis of literature on international policy concerning professional regulation in nursing and midwifery, with reference to routes of entry into training and pathways to licensure.

Background: Internationally, there is evidence of multiple points of entry into initial training, multiple divisions of the professional register and multiple pathways to licensure.

Evaluation: Policy documents and commentary articles concerned with models of initial training and pathways to licensure were reviewed.