PCBP1 regulates LIFR through FAM3C to maintain BCSC self-renewal and invasiveness
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ABSTRACT:
PROVIDER: PRJNA983496 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24912244_1.fastq.gz | Fastqsanger.gz | |||
| SRR24912244_2.fastq.gz | Fastqsanger.gz | |||
| SRR24912245_1.fastq.gz | Fastqsanger.gz | |||
| SRR24912245_2.fastq.gz | Fastqsanger.gz | |||
| SRR24912246_1.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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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
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