Identifying Novel Intensity-Specific Regulators of RAS Signaling

鉴定 RAS 信号传导的新型强度特异性调节因子

基本信息

批准号：
10350724
负责人：
Zahra Kabiri
金额：
$ 13.39万
依托单位：
DUKE UNIVERSITY
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：
2022-07-19 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10350724
关键词：
Biochemistry CRISPR/Cas technology Cancer Biology Cancer cell line Cells Codon Nucleotides Disease Drosophila genus Eye Family Family member Feedback Frequencies Genes Genetic Genetic Predisposition to Disease Genetic Translation Genetically Engineered Mouse Goals Growth Homologous Gene Human KRAS2 gene Libraries Link MAP Kinase Gene Malignant Neoplasms Mammalian Cell Maps Mediating Medicine Messenger RNA Monitor Monomeric GTP-Binding Proteins Mutate Mutation Oncogenic Output Pathology Pathway interactions Phenotype Positioning Attribute Post-Transcriptional Regulation Protein Subunits Proteins RAS genes RNA Interference RNA-Binding Proteins Regulation Research Research Personnel Ribosomal Proteins Ribosomes Risk Role Signal Transduction Testing Therapeutic Intervention Time Translations Tumor Suppressor Proteins biological adaptation to stress cancer initiation cancer therapy clinically relevant experience fascinate fly gene discovery in vivo knock-down mRNA Stability malignant phenotype multidisciplinary mutant new therapeutic target novel novel strategies novel therapeutics ras Proteins response screening senescence stem cell biology therapeutic target therapy resistant tumor initiation tumor progression tumorigenesis whole genome

项目摘要

Abstract The mammalian family of RAS small GTPases, composed of HRAS, NRAS, and KRAS, is mutated to remain in an active, oncogenic state in one fifth of all human cancers. Typically, these mutations occur early, initiating tumorigenesis. Of the three family members, KRAS is mutated most often, suggesting that some feature of this gene renders it more likely to initiate tumorigenesis. To this end, our group linked the high frequency with which KRAS is mutated to a bias of rare codons and resulting poor translation of the encoded mRNA. Mechanistically, the lower levels of KRAS protein and KRAS/MAPK signaling intensity circumvent the growth arrest response of senescence, thereby allowing the induction of tumor initiation. Conversely, poor translation of KRAS mRNA is overcome in later disease stages, promoting tumor progression. Thus, different levels of KRAS/MAPK signaling intensity dictate distinct phenotypic outputs during cancer initiation and progression. Therefore, there must be factors that differentially control Ras signaling intensity, and these factors should be critical during either tumor initiation or tumor progression. Such regulators are of great clinical relevance and could open up the door to a whole new class of regulators of Ras signaling for therapeutic intervention. My long-term goal is to identify and therapeutically target “RAS intensity-specific regulators”. To identify these regulators, our group took advantage of the incredible sensitivity of the Drosophila rough eye phenotype to differential levels of Ras signaling. We employed the novel approach of altering codon usage in the Ras gene of Drosophila to compare high and low Ras signaling. We then exploited these two genetic backgrounds to execute the first-ever in vivo intensity-specific regulator screen and identified fifteen deficiencies. One deficiency was mapped to the Ribosomal protein S21 (Rps21) gene, which acts as a suppressor of Ras signaling. I therefore plan to investigate the underlying mechanism by which Rps21 suppresses Ras signaling (Aim 1). In addition, I aim to identify other novel intensity-specific regulators of Ras signaling in the remaining deficiencies and elucidate their roles in Ras tumorigenesis in the mammalian setting (Aim 2). Completion of these aims will establish new connections between translational control and Ras signaling, reveal new genetic vulnerabilities in RAS-driven cancer, and finally could unearth a pipeline of potential therapeutic targets to explore for cancer therapies.

抽象的由HRA，NRA和KRAS组成的Ras小GTPases的哺乳动物家族被突变为在所有人类癌症的五分之一中，一种活跃的致癌状态。通常，这些突变发生早期发生，启动肿瘤发生。在这三个家庭成员中，克拉斯经常被突变，这表明其中一些特征基因使其更有可能启动肿瘤发生。为此，我们的小组链接了高频 KRAS被突变成稀有密码子的偏置，并导致编码的mRNA翻译不良。机械上， KRAS蛋白和KRAS/MAPK信号的较低水平避免了生长停滞响应感应，从而允许诱导肿瘤倡议。相反，Kras mRNA的不良翻译是在后来的疾病阶段克服，促进肿瘤进展。那，不同级别的KRAS/MAPK信号传导强度决定癌症开始和进展过程中不同的表型输出。因此，必须有控制RAS信号强度的因素以及这些因素在任何一种肿瘤期间都应至关重要起始或肿瘤进展。这样的监管机构具有很大的临床意义，可以为全新的RAS信号调节剂，用于治疗干预。我的长期目标是确定并以治疗目标为目标“ RAS强度特定调节剂”。为了确定这些监管机构，我们的小组接受了果蝇粗眼表型对RAS差异水平的令人难以置信的灵敏度的优势信号。我们采用新的方法来改变果蝇的RAS基因中的密码子使用来比较高和低RAS信号传导。然后，我们探索了这两个遗传背景，以执行有史以来第一个体内特定于强度的调节器屏幕并确定了15个缺陷。一个缺陷被映射到核糖体蛋白S21（RPS21）基因，它充当RAS信号的抑制剂。因此，我计划调查 RPS21抑制RAS信号传导的基本机制（AIM 1）。此外，我的目标是确定其他剩余缺陷中RAS信号传导的新型强度特异性调节剂，并阐明其在RAS中的作用哺乳动物环境中的肿瘤发生（AIM 2）。这些目标的完成将建立新的联系在翻译控制和RAS信号之间，揭示了由RAS驱动的癌症中的新遗传脆弱性，以及最终，可以发掘出潜在的治疗靶标的管道，以探索癌症疗法。