TGF-regulated EMT

TGF 调节的 EMT

• 批准号: 8784197
• 负责人: Philip H Howe
• 金额: $ 30.61万
• 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 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784197
• 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; Health; 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; 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（由适用提供）：上皮 - 间质转变（EMT），其中细胞从极化的上皮表型转变为胚胎发育过程中的高度运动成纤维细胞或间质表型是基本的，并且可以在包括纤维化和癌症在内的各种疾病中重新激活。 EMT与细胞细胞粘附的变化，细胞外基质的重塑以及增强的迁移活性有关，所有特性都可以使肿瘤细胞转移。 EMT中隐含了许多细胞因子和自分泌生长因子，包括TGF？。尽管对人肿瘤进行了密集的转录阵列分析，但“ EMT签名基因”的身份和验证仍然难以捉摸。我们已经阐明了一种新颖的转录后途径？调节EMT诱导蛋白和EMT本身的表达。 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 reflecting their translation in Nmumg和EPRAS细胞，两个建立的EMT体外模型。在这条路中，TGF？通过同工型特异性刺激蛋白激酶b。 /Akt2激活HNRNP E1 Ser43磷酸化的激酶级联反应，从而诱导其从BAT元件中释放并引起DAB2和ILEI mRNA的翻译激活。 HNRNP E1表达或其翻译后修饰的调节不仅改变了目标转录本的TGF介导的翻译激活，还改变了EMT。最近，我们纯化了与BAT元素结合的色带核蛋白（MRNP）复合物，并确定伸长因子1A1（EF1A1）是该翻译沉默途径的第二个功能成分。我们假设DAB2和ILEI的翻译调节以及其他EMT诱导者转录物构成了由HNRNP E1和EF1A1介导的TGFTH-tgfTO-tgf？可诱导的转录后调节，在肿瘤发生过程中在功能上调节EMT。该提案的目的是将这种MRNP复合物用作TGF信号的模型目标，以描述其对TGF响应的蛋白质合成的调节，并确定其在介导肿瘤发生和转移性进展中的功能意义。