TGF-regulated EMT

TGF 调节的 EMT

• 批准号: 8403717
• 负责人: Philip H Howe
• 金额: $ 28.77万
• 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/8403717
• 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; 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; public health relevance; 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-间质转化（EMT），其中细胞经历从极化的上皮表型到高度活动的成纤维细胞或间质表型的转变，这是胚胎发育过程中的基础，并且可以在多种疾病中重新激活包括纤维化和癌症在内的 EMT 与细胞间粘附的变化、细胞外基质的重塑和迁移活动的增强有关，所有这些特性都使肿瘤细胞能够发挥作用。尽管对人类肿瘤进行了深入的转录阵列分析，但“EMT 特征基因”的身份和验证仍然难以捉摸。 TGF? 调节 EMT 诱导蛋白表达和 EMT 本身的转录途径。与两个真正的 EMT 诱导转录物——disabled-2 (Dab2) 和白细胞介素样 EMT 诱导物 (ILEI) 的 3'-UTR 中的结构性 33 核苷酸 TGFbeta 激活翻译 (BAT) 元件结合，从而抑制它们的翻译在 NMuMG 和 EpRas 细胞（两种建立的 EMT 体外模型）中，TGF? 激活激酶级联，终止磷酸化。蛋白激酶 B 的亚型特异性刺激导致 hnRNP E1 的 Ser43 /Akt2，诱导其从 BAT 元件中释放并引起 Dab2 和 ILEI mRNA 的翻译激活 hnRNP E1 表达的调节或其翻译后修饰不仅改变 TGF¿最近，我们纯化了与 BAT 元件结合的核糖核蛋白 (mRNP) 复合物，并确定了延伸因子 1A1 (EF1A1) 作为该翻译沉默途径的第二个功能成分。我们认为 Dab2 和 ILEI 以及其他 EMT 诱导转录物的翻译调控构成了 TGF¿ - 由 hnRNP E1 和 EF1A1 介导的诱导型转录后调节子，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 mRNA 复合物作为 TGF 的模型靶标。信号传导，以描述其对 TGF 反应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。