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 项目负责人：Sharon L.坎贝尔 翻译后摘要：RAS基因编码的小21 kD的GTP酶之间的循环活动和非活动状态，以调节 细胞生长大约三分之一的人类癌症在RAS基因中含有激活突变， 密码子热点位于位置12、13和61。这些点突变使得RAS蛋白对下调不敏感。 调节，导致慢性RAS激活和组成性致癌信号传导。因此，他们 历史上被认为是致癌等同物。然而，最近的观察表明，密码子和 残基特异性RAS突变的不同之处在于它们作为GTP酶开关、接合效应物和 促进信号传导和肿瘤发生。在对下列问题的反应和抵制方面也观察到了差异： 具体的抗癌疗法。因此，了解这些差异将具有重要的临床和生物 影响同样令人感兴趣的是，癌症在RAS突变和基因突变中表现出组织特异性偏好。 同种型为了更好地了解癌症特异性RAS突变和亚型差异，我们提出 KRAS和NRAS亚型的结构和生化表征研究。这些研究报告将 与P01的其他组分高度整合，并包括基于细胞和小鼠的研究， 分子信息与RAS激活水平，RAS介导的信号传导和肿瘤发生。在目标1中，我们 确定NRAS和KRAS中密码子和残基特异性致癌突变是否差异性改变 内在RAS功能和效应物识别。在目标2中，我们将确定 NRAS和KRAS的核心GT3结构域驱动内在RAS功能的同种型特异性差异， 信号传导和肿瘤发生。在目的3中，我们将确定如何活性和肿瘤促进性质的 KRAS和肺癌中常见的致癌KRAS突变体（G12 C）受半胱氨酸氧化调节。 KRAS G12 C的氧化还原特性的表征将有助于抗癌工作，以靶向这种致癌基因。 突变体，以及理解在基于细胞和小鼠中观察到的KRAS G12C的不同表型 模型研究拟议的研究将有助于阐明密码子，残基和异构体特异性差异， 促进RAS驱动的癌症，这将为开发新的和更具体的治疗方法提供信息， RAS功能异常的癌症。

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.