PCBP1 regulates LIFR through FAM3C to maintain BCSC self-renewal and invasiveness
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PROVIDER: PRJNA983496 | ENA |
REPOSITORIES: ENA
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Project description:The poly(rC) binding protein 1 gene (PCBP1) encodes the heterogenous nuclear ribonucleoprotein E1 (hnRNPE1), a nucleic acid binding protein that plays a tumor-suppressive role in mammary epithelium by regulating phenotypic plasticity and cell fate. Following 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 the signal transducer and activator of transcription 3 (pSTAT3). The overexpression and/or hyperactivity of STAT3 has been detected in 40% of breast cancer cases and is associated with poor prognosis. Herein, we characterize feed-forward regulation of LIFR expression in response to FAM3C/LIFR/pSTAT3 signaling in mammary epithelial cells, and show that PCBP1 upregulates LIFR transcription through FAM3C, involving activity at the LIFR promoter. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with FAM3C/LIFR interaction and identifies the TWIST1 transcription factor as a downstream effector that participates in maintenance of LIFR expression. Finally, we characterize the effect of LIFR expression in cell-based experiments that demonstrate promotion of invasion, migration, and breast cancer stem cell (BCSC) self-renewal, consistent with previous studies that link LIFR expression to tumor initiation and metastasis in mammary epithelial cells.
2023-06-13 | GSE234882 | GEO
Project description:Dlx3 over-expression in mouse embryonic fibroblasts changed the expression level of numerous genes involved in osteogenesis and embryonic stem cell-related pathways as revealed by microarray analysis. From the list of Dlx3 modulated genes we focused our attention on the study of two candidates, Lifr and Chrdl1. Chromatin immunoprecipitation demonstrated the recruitment of Dlx3 transcription factor to the promoters of Lifr and Chrdl1, and luciferase assays confirmed the role of Dlx3 in the regulation of Lifr expression. Over-expression of Dlx3 in mouse embryonic stem cells stimulated Lifr and Chrdl1 expression and inhibited expression of Id proteins and Bmp4. We show that Dlx3 increases the expression of both soluble and transmembrane forms of Lifr. Soluble Lifr may regulate extracellular Lif levels via solution binding, while transmembrane Lifr mediates the signal transduction pathway. The data suggests that Dlx3 may be involved in stem cell differentiation in a dosage dependent way through its interaction with Lifr and with Chrdl1, a known antagonist of Bmp4. We speculate that Dlx3 may also be involved in osteoblast differentiation through interactions involving Lifr, Bmp, and Id proteins and signaling via the JAK/STAT and MAPK pathways. In summary, our data suggests that Dlx3 proteins play a significant role in a highly tuned network in early embryogenesis. Keywords: treated vs.untreated Stable and Transient transfection of Dlx3 in MEF. Total of 4 hybridizations including biological replicates.
2009-08-15 | E-GEOD-11727 | biostudies-arrayexpress
Project description:MCF7 cells were infected with lentiviral particles containing LIFR-targeted shRNAs then chemically selected to create a stable pooled population of shLIFR MCF7 cells. The goal of the study was to determine the downstream targets of LIFR in human MCF7 breast cancer cells.
2024-05-03 | GSE174592 | GEO
Project description:RNA-binding proteins participate in a complex array of post-transcriptional controls essential to cell-type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts on mammalian embryonic development remains incompletely defined and the level of functional redundancy among subsets of these proteins remains open to question. The poly-(C) binding proteins, Pcbp's (aCPs, hnRNPEs), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos survive until mid-gestation at which time they undergo a loss in viability associated with cardiovascular and hematopoietic abnormalities. Adult mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and non-disruptive growth defect. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and post-natal growth, reveal a non-redundant in vivo role for Pcpb2 in hematopoiesis, and provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved essential function(s) in the mammalian genome. mRNA-seq on fetal liver tissue from 12.5 days post coitum. 4 replicates of WT and 3 replicates of PCBP2 Knockout
2015-11-05 | E-GEOD-72491 | biostudies-arrayexpress
Project description:Elucidating the mechanism of self-renewal and pluripotency maintenance of human embryonic stem cells (hESCs) is of great significance in basic research and clinical applications. Long non-coding RNAs (lncRNAs) have been shown to play a key role in the self-renewal and pluripotency maintenance of hESCs. We previously reported that the lncRNA ESRG, which is highly expressed in undifferentiated hESCs, can interact with the replication licensing factor MCM2 and inhibit the p53 pathway to maintain the self-renewal and pluripotency of hPSCs. In addition to MCM2, RNA pull-down mass spectrometry showed that ESRG could also bind to other proteins, among which heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) attracted our attention. In this study, we show that HNRNPA1 can maintain self-renewal and pluripotency of hESCs. ESRG binds to and stabilizes HNRNPA1 protein through the ubiquitin-proteasome pathway. In addition, knockdown of ESRG or HNRNPA1 resulted in alternative splicing of TCF3, which originally and primarily encodes E12, to mainly encode E47 and inhibit CDH1 expression. HNRNPA1 could rescue the biological function changes of hESCs caused by ESRG knockdown or overexpression. Our results suggest that ESRG regulates the alternative splicing of TCF3 to affect CDH1 expression and maintain hESCs self-renewal and pluripotency by binding and stabilizing HNRNPA1 protein. This study lays a good foundation for exploring the new molecular regulatory mechanism by which ESRG maintains hESCs self-renewal and pluripotency.
2024-03-05 | GSE236745 | GEO
Project description:Wnt signaling, which drives the rapid self-renewal of the gut epithelium is causally associated with intestinal neoplasia. Here we show that CKIalpha is a activation depends on p53 and p21Waf1/Cip1: CKIα ablation provokes activation of p53 and p21, which assume a pivotal role in suppressing invasive cancer. Dual loss of CKIalpha and either p53 or p21 results in rapid, rampant malignant signature denoted p53supinv (p53-suppressed invasiveness) that is conditionally induction of invasiveness. Like invasiveness control, the transcriptional suppression of p53supinv genes is largely mediated by p21, independently of cell cycle control, representing a novel tumor suppressor function of wild-type p53. 13 arrays of mice entrocytes herto or homozygot for gut specific KO of CKI alpha. Crossed with p53 or p21 KO mice.
2010-10-23 | E-GEOD-24760 | biostudies-arrayexpress
Project description:Wnt signaling, which drives the rapid self-renewal of the gut epithelium is causally associated with intestinal neoplasia. Here we show that CKIalpha is a activation depends on p53 and p21Waf1/Cip1: CKIα ablation provokes activation of p53 and p21, which assume a pivotal role in suppressing invasive cancer. Dual loss of CKIalpha and either p53 or p21 results in rapid, rampant malignant signature denoted p53supinv (p53-suppressed invasiveness) that is conditionally induction of invasiveness. Like invasiveness control, the transcriptional suppression of p53supinv genes is largely mediated by p21, independently of cell cycle control, representing a novel tumor suppressor function of wild-type p53.
2010-10-23 | GSE24760 | GEO
Project description:Iron deposition is frequently observed in human autoinflammatory diseases, such as in the brain of patients with multiple sclerosis or in the synovial fluid of patients with rheumatoid arthritis1-5. Yet, the functional outcome of excessive iron in inflammatory conditions is largely unknown. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine promoting myeloid cell maturation and activation6 and is essential for the pathogenesis of many autoimmune diseases, including autoimmune encephalomyelitis7-10. Post-transcriptional regulation of GM-CSF is mediated primarily through its 3’ untranslated region (3’UTR) via interaction with specific RNA-binding proteins11. Here we show that a RNA-binding protein PCBP1 senses intracellular iron and post-transcriptionally promotes GM-CSF production. In a short hairpin (sh) RNA screening, we found that Poly(rC) binding protein 1 (PCBP1) enhanced GM-CSF 3’UTR activity and its endogenous mRNA stability. PCBP1 deficiency in autoreactive T cells resulted in a compromised production of GM-CSF and other proinflammatory cytokines, abolishing their capacity in inducing experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Using Crosslinking and Immunoprecipitation (CLIP)12, we demonstrated that PCBP1 promoted mRNA stability by recognizing CU rich elements in the 3’UTRs of pro-inflammatory cytokines. Furthermore, iron depletion induced rapid caspase-mediated proteolysis of PCBP1 and inhibited the production of GM-CSF and a module of 24 cytokines in primary murine and human T cells. Our study thus demonstrates that PCBP1 is critical for the post-transcriptional regulation of proinflammatory cytokines, and indicates that sensing iron may represent a simple yet effective means to adjust the inflammatory response to tissue homeostatic alterations.
2018-07-04 | GSE84699 | GEO
Project description:Dlx3 over-expression in mouse embryonic fibroblasts changed the expression level of numerous genes involved in osteogenesis and embryonic stem cell-related pathways as revealed by microarray analysis. From the list of Dlx3 modulated genes we focused our attention on the study of two candidates, Lifr and Chrdl1. Chromatin immunoprecipitation demonstrated the recruitment of Dlx3 transcription factor to the promoters of Lifr and Chrdl1, and luciferase assays confirmed the role of Dlx3 in the regulation of Lifr expression. Over-expression of Dlx3 in mouse embryonic stem cells stimulated Lifr and Chrdl1 expression and inhibited expression of Id proteins and Bmp4. We show that Dlx3 increases the expression of both soluble and transmembrane forms of Lifr. Soluble Lifr may regulate extracellular Lif levels via solution binding, while transmembrane Lifr mediates the signal transduction pathway. The data suggests that Dlx3 may be involved in stem cell differentiation in a dosage dependent way through its interaction with Lifr and with Chrdl1, a known antagonist of Bmp4. We speculate that Dlx3 may also be involved in osteoblast differentiation through interactions involving Lifr, Bmp, and Id proteins and signaling via the JAK/STAT and MAPK pathways. In summary, our data suggests that Dlx3 proteins play a significant role in a highly tuned network in early embryogenesis. Keywords: treated vs.untreated
2009-08-15 | GSE11727 | GEO
Project description:MCF7 cells with LIFR knockdown
| PRJNA730596 | ENA