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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结/文摘