Project 2: Role of codon and isoform differences in Ras tumorigenesis

项目2：密码子和亚型差异在Ras肿瘤发生中的作用

• 批准号: 9488433
• 负责人: Sharon L Campbell
• 金额: $ 12.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9488433
• 关键词: Alkylating Agents; Amino Acids; Antineoplastic Agents; Biochemical; Biological; Cell Proliferation; Cell model; Cells; Chronic; Clinical; Codon Nucleotides; Collaborations; Cysteine; Defect; Development; Down-Regulation; Drug Targeting; Family; Fibroblasts; GTP Binding; GTPase-Activating Proteins; Growth; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; KRAS2 gene; Knock-in Mouse; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Oncogenes; Oncogenic; Organ; Oxidants; Oxidation-Reduction; Phenotype; Physiological; Point Mutation; Positioning Attribute; Post-Translational Protein Processing; Property; Protein Isoforms; Proteins; RAS genes; Regulation; Reporting; Resistance; Role; Signal Transduction; Site; Structure; Study models; Sulfhydryl Compounds; Tissues; Tumor Tissue; Tumorigenicity; anti-cancer; base; cancer therapy; cell growth; design; melanoma; mouse model; mutant; oxidation; preference; protein function; ras Proteins; response; tumor; tumor xenograft; tumorigenesis; tumorigenic; ultraviolet damage

Project 2: Role of codon and isoform differences in RAS tumorigenesis Project Leader: Sharon L. Campbell Abstract: RAS genes encode small 21 kD GTPases that cycle between active and inactive states to regulate cellular growth. Approximately one-third of all human cancers contain activating mutations in RAS genes, with codon hotspots at positions 12, 13 and 61. These point mutations render RAS proteins insensitive to down regulation, resulting in chronic RAS activation and constitutive, oncogenic signaling. As such, they have historically been considered oncogenic equivalents. However, recent observations suggest that codon- and residue-specific RAS mutations differ in their ability to function as GTPases switches, engage effectors, and promote signaling and tumorigenesis. Differences have also been observed in the response and resistance to specific anti-cancer therapies. Thus understanding these differences will have important clinical and biological implications. It is also intriguing that cancers display tissue-specific preferences in both RAS mutation and isoform type. To better understand cancer-specific RAS mutation and isoform differences, we propose structural and biochemical characterization studies on the KRAS and NRAS isoforms. These studies will be highly integrated with other components of the P01, and include cell-based and mouse studies to correlate molecular information with RAS activation levels, RAS-mediated signaling and tumorigenesis. In Aim 1, we will determine whether codon- and residue-specific oncogenic mutations in NRAS and KRAS differentially alter intrinsic RAS function and effector recognition. In Aim 2, we will determine whether sequence differences in the core GTPase domain of NRAS and KRAS drive isoform-specific differences in intrinsic RAS function, signaling and tumorigenesis. In Aim 3, we will determine how the activity and tumor promoting properties of KRAS and an oncogenic KRAS mutant (G12C) prevalent in lung cancer are regulated by cysteine oxidation. Characterization of the redox properties of KRAS G12C will aid in anti-cancer efforts to target this oncogenic mutant, as well as understanding distinct the phenotypes of KRAS G12C observed in cell-based and mouse model studies. The proposed studies will help elucidate codon-, residue- and isoform-specific differences that promote RAS-driven cancers, which will inform the development of new and more specific therapies to target aberrant RAS function in cancer.

项目2：密码子和同工型在RAS肿瘤发生中的作用 项目负责人：沙龙·坎贝尔（Sharon L. Campbell） 摘要：RAS基因编码小的21 kD GTP酶，该GTP酶在活动状态和非活动状态之间循环以调节 细胞生长。大约三分之一的人类癌症包含RAS基因中的激活突变， 位置12、13和61处的密码子热点。这些点突变使RAS蛋白对下降不敏感 调节，导致慢性RAS激活和构成性的致癌信号传导。因此，他们有 从历史上看，造型等效物被认为是。但是，最近的观察表明密码子和 残留特异性的RAS突变在其作为GTPases开关，互动效应子和 促进信号传导和肿瘤发生。在反应和抵抗力中也观察到了差异 特定的抗癌疗法。因此，了解这些差异将具有重要的临床和生物学 含义。同样有趣的是，癌症在RAS突变和 同工型类型。为了更好地了解癌症特异性的RAS突变和同工型差异，我们提出 关于KRAS和NRA同工型的结构和生化表征研究。这些研究将是 与P01的其他组件高度集成，并包括基于细胞的和小鼠研究以相关 RAS激活水平，RAS介导的信号传导和肿瘤发生的分子信息。在AIM 1中，我们将 确定NRA和KRAS中的密码子和残基特异性致癌突变是否会改变 固有的RAS功能和效应子识别。在AIM 2中，我们将确定序列差异是否存在 NRAS和KRAS驱动力特异性RAS功能的核心GTPase结构域， 信号传导和肿瘤发生。在AIM 3中，我们将确定活动和肿瘤促进特性如何 肺癌中普遍存在的KRAS和致癌性KRAS突变体（G12C）受半胱氨酸氧化的调节。 KRAS G12C的氧化还原特性的表征将有助于抗癌作用，以瞄准这种致癌性 突变体以及在基于细胞和小鼠中观察到的KRAS G12C的表型明显 模型研究。拟议的研究将有助于阐明密码子，残基和同工型特异性差异， 推广以RAS为导向的癌症，这将为您的新疗法开发以靶向靶向 癌症的异常RAS功能。