Dynamics of Gene and Isoform Regulation during EMT and tumor progression

EMT 和肿瘤进展过程中基因和亚型调控的动态

• 批准号: 8852097
• 负责人: CHRISTOPHER B BURGE
• 金额: $ 69.39万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852097
• 关键词: 3' Untranslated Regions; Address; Affect; Aggressive behavior; Algorithms; Alternative Splicing; Amino Acid Sequence; Apoptosis; Behavioral; Bioinformatics; Biological; Biological Assay; Biological Markers; Breast Cancer Model; Breast Epithelial Cells; Cancer Patient; Cell model; Cells; Cellular Morphology; Code; Complex; Cultured Cells; Cytoskeleton; Data; Data Analyses; Data Set; Development; Distant; Elements; Epithelial; Epithelial Cells; Equipment and supply inventories; Event; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Human; Image; Immunofluorescence Immunologic; In Vitro; Intercellular Junctions; Life; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mesenchymal; Messenger RNA; Metastatic breast cancer; MicroRNAs; Modeling; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Nucleotides; Pathway interactions; Peptide Sequence Determination; Phenotype; Phosphorylation; Physiology; Play; Primary Neoplasm; Process; Production; Property; Protein Isoforms; Proteins; RNA; RNA Binding; RNA Splicing; RNA-Binding Proteins; Regulation; Reporter; Research; Resistance; Role; Seeds; Series; Set protein; Signal Pathway; Signal Transduction; Site; Snails; Spliced Genes; Stem cells; Structure; Testing; Therapeutic; Tissues; Transgenes; Transgenic Mice; Untranslated Regions; Work; cancer cell; cell behavior; cell motility; cohort; design; epithelial to mesenchymal transition; extracellular; gene function; in vivo; insight; mRNA Stability; neoplastic cell; novel; programs; protein expression; protein protein interaction; response; transcription factor; transcriptome sequencing; tumor; tumor progression

DESCRIPTION (provided by applicant): The epithelial-mesenchymal transition (EMT) is a complex cell-biological program that operates during the progression of carcinoma cells to high-grade malignancy, conferring on these cells many of the attributes associated with aggressive tumors, including the ability to disseminate to distant sites and to seed metastatic colonies. This program is orchestrated by a series of pleiotropically acting master transcription factors (EMT- TFs) that organize the complex changes in gene expression causing the replacement of a large cohort of epithelial cell proteins with those associated with the mesenchymal cell state. A major, critical level of control required for expression of the aggressive mesenchymal state is poorly understood however: the precursors of many of the mRNAs whose expression changes during the EMT also undergo alternative splicing (AS) that confer on resulting mature, processed mRNAs altered properties, including changes in stability, protein-coding information, and responsiveness to microRNA-mediated inhibition. The current fragmentary insights into the effects of AS on the execution of the EMT program make it impossible to form a reasonably complete understanding of how this critical cell-biological program is effected. The proposed research will begin by enumerating the hundreds of AS events that occur in response to several alternative mechanisms of inducing an EMT program both in cultured cells and in a living tissue. Having done so, bioinformatics algorithms will be employed to determine the sequences adjacent to involved splice sites. Thereafter, using the known nucleotide-recognizing properties of the large array of already-characterized RNA- binding, splice-regulating proteins, predictions will be made by these algorithms about the identities of the splice-regulators that are likely to b responsible for the observed large-scale shifts in AS occurring during passage through an EMT. This experimental strategy should yield the identities of key regulators of AS that are likely to b as important functionally as the EMT-TFs in executing the EMT program. Experimental tests designed to functionally test the candidacies of these AS factors will be performed. These tests will gauge whether the forced or blocked expression of these factors affect execution of critical components of the EMT program, and whether, as predicted, such imposed changes in AS factor expression affect the production of key EMT-associated proteins, i.e., proteins that play key roles in the expression of the epithelial versus mesenchymal cell phenotypes observed during malignant progression. This work also has the potential to identify novel biomarkers of the EMT program that are applicable, for example, for the detections of stem cells in a variety of epithelial tissues.

描述（由申请人提供）：上皮-间质转化（EMT）是一个复杂的细胞生物学程序，在癌细胞向高级别恶性肿瘤的进展过程中起作用，赋予这些细胞许多与侵袭性肿瘤相关的属性，包括向远处扩散和转移集落种子的能力。这