Regulation of Human Tumorigensis by Cancer Specific NXF1 Adaptor Proteins

癌症特异性 NXF1 接头蛋白对人类肿瘤发生的调节

• 批准号: 10411472
• 负责人: GEORGE L SEN
• 金额: $ 36.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411472
• 关键词: 3' Untranslated Regions; 3-Dimensional; Adaptor Signaling Protein; Address; Apoptosis; Applications Grants; Automobile Driving; Basement membrane; Binding; Binding Proteins; Cell Line; Cell Survival; Cells; Code; Complex; Cytoplasm; Data; Dermal; Disease; Epidermis; Family; Gene Expression; Generations; Genes; Genetic Transcription; Growth; Human; Immune; Lead; MAP Kinase Gene; Malignant Neoplasms; Mediating; Melanoma Cell; Messenger RNA; Mitosis; Modeling; Molecular; Mus; Mutation; Natural regeneration; Neoplasms; Normal tissue morphology; Nuclear Pore Complex; Oncogenic; Output; Pathway interactions; Process; Proteins; RNA; Regulation; Reporting; Research Design; Role; Signal Transduction; Skin; Specificity; Squamous cell carcinoma; Transcript; Translating; Tumor stage; Tumor-Derived; VEGFC gene; cancer diagnosis; cell motility; clinically relevant; crosslinking and immunoprecipitation sequencing; design; experimental study; human model; in vivo; insight; knock-down; loss of function; mRNA Export; member; neoplastic; new technology; overexpression; pluripotency; programs; protein complex; stem; therapeutic target; therapy development; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis

Project Summary/Abstract Background: Cancer originates from genetic alterations that lead to changes in gene expression programs that promote tumor survival, growth, motility and inhibits differentiation and apoptosis. The mRNAs from this oncogenic gene expression program must be exported to the cytoplasm to be translated into protein in order to promote tumorigenesis. Whether there is regulation of export of tumor specific mRNAs and the potential proteins involved in this process is unknown. We have shown that tumor specific NXF1 adaptor proteins regulate export of oncogenic mRNAs. The adaptor proteins are also highly upregulated during tumor initiation and knockdown of specific adaptors inhibit tumorigenesis. Objective/hypothesis: This proposal seeks to understand the molecular mechanisms driving the progression from normal to neoplastic skin using a RAS driven human epidermal tumor model. Our preliminary data suggests that 4 adaptor proteins are highly upregulated during tumor initiation that associates with NXF1 to mediate the export of the oncogenic gene expression program. Our objective is to characterize the role of each tumor induced NXF1 adaptor protein in the progression of normal to neoplastic skin. Furthermore we seek to determine the specific transcripts that each adaptor protein binds during tumor initiation to promote tumorigenesis. Specific Aims: (1) To determine the role of NXF1 adaptor proteins in the progression from normal to neoplastic skin and (2) to identify the transcripts associated with NXF1 adaptor proteins and determine which bound transcripts are exported. Study Design: To study epidermal tumorigenesis in a more clinically relevant setting, we generate 3-dimensionally intact human skin, containing human epidermal cells (that have been permanently knocked down for adaptor proteins) in the context of human dermal stroma and basement membrane, regenerated on immune compromised mice. By using this model, we can perform loss of function experiments on NXF1 adaptor proteins in regenerated human skin to characterize their role in epidermal growth, differentiation, and progression to neoplasia. We will use CLIP-Seq to determine the RNAs associated with each adaptor protein during the progression from normal to neoplastic epidermis.

项目摘要/摘要 背景：癌症来自导致基因变化的遗传改变 促进肿瘤生存，生长，运动和抑制的表达程序 分化和凋亡。该致癌基因表达程序的mRNA 必须将其导出到细胞质中才能翻译成蛋白质，以促进 肿瘤发生。是否有调节肿瘤特异性mRNA和 参与此过程的潜在蛋白质尚不清楚。我们已经表明肿瘤 特定的NXF1适配器蛋白调节致癌mRNA的出口。适配器 蛋白质在肿瘤开始期间也高度上调和敲低特异性 适配器抑制肿瘤发生。 客观/假设：该提议旨在理解分子机制 使用RAS驱动的人来推动从正常到肿瘤皮肤的进展 表皮肿瘤模型。我们的初步数据表明4种适配器蛋白高度高 在肿瘤开始期间与NXF1相关的肿瘤开始上调 致癌基因表达程序。我们的目标是表征 每个肿瘤在正常到肿瘤的进展中诱导NXF1衔接蛋白 皮肤。此外，我们试图确定每个衔接蛋白的特定转录本 结合肿瘤起源以促进肿瘤发生。 具体目的：（1）确定NXF1适配器蛋白在进展中的作用 从正常到肿瘤皮肤和（2）识别与NXF1相关的转录本 适配器蛋白并确定输出哪些结合的转录本。 研究设计：在更临床相关的环境中研究表皮肿瘤发生， 我们产生3维完整的人皮，其中包含人类表皮细胞（ 在人类的背景下，已永久击倒适配器蛋白 皮肤基质和基底膜，在免疫受损小鼠上再生。 通过使用此模型，我们可以在NXF1适配器上执行功能实验的丢失 再生的人皮中的蛋白质以表征其在表皮生长中的作用， 分化和向肿瘤的发展。我们将使用夹式来确定 从正常到 肿瘤表皮。