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: 10596156
• 负责人: GEORGE L SEN
• 金额: $ 35.42万
• 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/10596156
• 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 Promotion; Tumor stage; VEGFC gene; Vascular Endothelial Growth Factor C; 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.

项目概要/摘要 背景：癌症起源于导致基因改变的基因改变 促进肿瘤存活、生长、运动和抑制的表达程序 分化和凋亡。来自该致癌基因表达程序的 mRNA 必须输出到细胞质翻译成蛋白质才能促进 肿瘤发生。肿瘤特异性 mRNA 的输出是否受到调控以及 参与该过程的潜在蛋白质尚不清楚。我们已经证明肿瘤 特定的 NXF1 接头蛋白调节致癌 mRNA 的输出。适配器 在肿瘤发生和特定基因敲低过程中，蛋白质也会高度上调。 接头抑制肿瘤发生。 目标/假设：该提案旨在了解分子机制 使用 RAS 驱动的人类驱动从正常皮肤到肿瘤皮肤的进展 表皮肿瘤模型。我们的初步数据表明 4 种接头蛋白具有高度 在肿瘤发生过程中上调，与 NXF1 相关联，介导 致癌基因表达程序。我们的目标是描述角色的特征 每个肿瘤在正常细胞向肿瘤细胞进展过程中都会诱导 NXF1 接头蛋白 皮肤。此外，我们试图确定每个接头蛋白的特定转录本 在肿瘤发生过程中结合以促进肿瘤发生。 具体目标： (1) 确定 NXF1 衔接蛋白在进展中的作用 从正常皮肤到肿瘤皮肤以及 (2) 识别与 NXF1 相关的转录本 接头蛋白并确定导出哪些结合的转录本。 研究设计：为了在更具临床相关性的环境中研究表皮肿瘤的发生， 我们生成 3 维完整的人类皮肤，其中包含人类表皮细胞（即 在人类环境中，接头蛋白已被永久敲除） 真皮基质和基底膜在免疫受损的小鼠身上再生。 通过使用该模型，我们可以在NXF1适配器上进行功能损失实验 再生人类皮肤中的蛋白质来表征它们在表皮生长中的作用， 分化，并进展为肿瘤。我们将使用 CLIP-Seq 来确定 从正常到正常的进展过程中与每个接头蛋白相关的RNA 肿瘤性表皮。