TGF-regulated EMT

TGF 调节的 EMT

• 批准号: 8327940
• 负责人: Philip H Howe
• 金额: $ 19.58万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327940
• 关键词: Binding; Biochemical; Biological Assay; Biological Process; Cancer Biology; Cell Proliferation; Cell-Cell Adhesion; Cells; Complex; Development; Disabled Persons; Disease; Elements; Embryonic Development; Epithelial; Extracellular Matrix; Family; Fibrosis; Genes; Genetic Translation; Goals; Growth Factor; Heterogeneous-Nuclear Ribonucleoproteins; Human; Hypoxia; In Vitro; Indium; Inflammation; Interleukin-2; Knowledge; Maintenance; Malignant Neoplasms; Maps; Mediating; Mesenchymal; Messenger RNA; Modeling; Molecular; Neoplasm Metastasis; Nucleotides; Nutrient; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Prevention; Process; Property; Protein Biosynthesis; Protein Isoforms; Protein Kinase; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; RNA-Protein Interaction; Receptor Signaling; Regulation; Regulatory Pathway; Regulon; Ribonucleoproteins; Role; Signal Transduction; Site; Structure; System; Techniques; Testing; Therapeutic; Tissues; Transcript; Transforming Growth Factor beta; Translational Activation; Translational Regulation; Translations; Tumor Angiogenesis; Untranslated Regions; Up-Regulation; Validation; autocrine; cancer cell; cell growth; cohort; cytokine; deprivation; design; human EEF1A1 protein; in vitro Model; in vivo; insight; messenger ribonucleoprotein; migration; neoplastic cell; novel; response; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The epithelial-mesenchymal transition (EMT), in which cells undergo a switch from a polarized, epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including fibrosis and cancer. EMT is associated with changes in cell-cell adhesion, remodeling of extracellular matrix, and enhanced migratory activity, all properties that enable tumor cells to metastasize. Numerous cytokines and autocrine growth factors, including TGF?, have been implicated in EMT. Despite intensive transcriptional array analysis of human tumors, the identity and validation of 'EMT signature genes' remains elusive. We have elucidated a novel, post-transcriptional pathway by which TGF? modulates expression of EMT-inducer proteins and EMT itself. We identified that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds to a structural, 33-nucleotide TGFbeta-activated translation (BAT) element in the 3'-UTR of two bona fide EMT-inducer transcripts, disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI), thereby repressing their translation in NMuMG and EpRas cells, two established in vitro models of EMT. In this pathway, TGF? activates a kinase cascade terminating in phosphorylation of Ser43 of hnRNP E1 by isoform-specific stimulation of protein kinase B¿/Akt2, inducing its release from the BAT element and causing translational activation of Dab2 and ILEI mRNAs. Modulation of hnRNP E1 expression, or its post-translational modification, alters not only TGF¿-mediated translational activation of the target transcripts, but also EMT. Recently, we have purified the ribonucleoprotein (mRNP) complex binding to the BAT element and have identified elongation factor 1A1 (EF1A1) as a second, functional component of this translational silencing pathway. We hypothesize that translational regulation of Dab2 and ILEI, as well as other EMT-inducer transcripts, constitutes a TGF¿-inducible post-transcriptional regulon mediated by hnRNP E1 and EF1A1, which functionally regulates EMT during tumorigenesis. The goal of this proposal is to use this mRNP complex as a model target of TGF¿ signaling, to delineate its regulation of protein synthesis in response to TGF¿ and to determine its functional significance in mediating tumorigenesis and metastatic progression.

描述（由申请人提供）：上皮-间充质转化（EMT）是胚胎发育过程中的基础，其中细胞经历从极化的上皮表型到高度能动的成纤维细胞或间充质表型的转变，并且可以在包括纤维化和癌症在内的多种疾病中重新激活。EMT与细胞间粘附、细胞外基质重塑和迁移活性增强的变化相关，所有这些特性都使肿瘤细胞能够转移。多种细胞因子和自分泌生长因子，包括TGF？，与急救队有牵连尽管对人类肿瘤进行了深入的转录阵列分析，但“EMT标签基因”的身份和验证仍然难以捉摸。我们已经阐明了一种新的，转录后途径，TGF？调节EMT诱导蛋白和EMT本身的表达。我们发现，异质性核核糖核蛋白E1（hnRNP E1）结合到两个真正的EMT诱导剂转录物（disabled-2（Dab 2）和白细胞介素样EMT诱导剂（ILEI））的3 '-UTR中的结构性33-核苷酸TGF β激活翻译（BAT）元件，从而抑制它们在NMuMG和EpRas细胞（两种已建立的EMT体外模型）中的翻译。在这条通路中，TGF？通过蛋白激酶B/Akt 2的同种型特异性刺激激活终止于hnRNP E1的Ser 43磷酸化的激酶级联，诱导其从BAT元件释放并引起Dab 2和ILEI mRNA的翻译激活。hnRNP E1表达的调节或其翻译后修饰不仅改变了TGF β介导的靶转录物的翻译活化，而且改变了EMT。最近，我们已经纯化的核糖核蛋白（mRNP）复合物的BAT元件结合，并已确定延伸因子1A 1（EF 1A 1）作为第二个，功能组件的翻译沉默途径。我们假设Dab 2和ILEI的翻译调节，以及其他EMT诱导转录物，构成了由hnRNP E1和EF 1A 1介导的TGF β诱导的转录后调节子，其在肿瘤发生过程中功能性调节EMT。该提案的目标是使用这种mRNP复合物作为TGF β信号传导的模型靶标，以描述其响应TGF β的蛋白质合成的调节，并确定其在介导肿瘤发生和转移进展中的功能意义。