Regulation of tumor promotion by RasGRP1

RasGRP1 对肿瘤促进的调节

基本信息

批准号：
8125991
负责人：
PATRICIA S LORENZO
金额：
$ 28.48万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-02 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8125991
关键词：
1,2-diacylglycerol 3-Dimensional Affinity Biochemical Biology Carcinogens Cells Chemoprevention Diglycerides Engineering Epidermal Growth Factor Receptor Epidermis Family Goals Grant Growth Factor Guanine Nucleotide Exchange Factors Guanosine Triphosphate Homeostasis Human Induced Mutation Inflammation Intervention Lead Ligands Link Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Target Mus Mutate Mutation Nature Oncogenes Oncogenic Pathway interactions Phorbol Esters Play Predisposition Protein Isoforms Protein Kinase C Proto-Oncogenes Ras Signaling Pathway Regulation Role Signal Pathway Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Staging System Tetradecanoylphorbol Acetate Therapeutic Therapeutic Intervention Transgenic Mice Tumor Promoters Tumor Promotion Tumor Suppressor Genes cancer therapy carcinogenesis cytokine dosage human disease in vitro Model keratinocyte mimetics mouse model novel overexpression phorbol ester receptor receptor response skin squamous cell carcinoma therapeutic target tumor tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The mouse model of skin carcinogenesis has served to investigate the multistage nature of tumorigenesis and to identify novel oncogenes and tumor suppressor genes, as well as signaling pathways relevant in cancer. In the classic two-stage carcinogenesis model, Ras is activated by mutations induced by a carcinogen, and subsequent treatment with phorbol esters induces tumor promotion. However, the mechanisms that lead to tumor formation of cells initiated by Ras -and the participation of phorbol ester signaling pathways- are still poorly understood. Using the mouse skin model, we have identified RasGRP1 as a novel regulator of skin carcinogenesis. RasGRP1 links phorbol esters and Ras, since it is both, a high affinity phorbol ester receptor and a Ras activator. Using genetically modified mice we have shown that RasGRP1 participates in tumor initiation and progression in the two-stage carcinogenesis model through the biochemical activation of wild type Ras. Additionally, transgenic mice overexpressing RasGRP1 in the epidermis are prone to develop skin tumors spontaneously. Taken together, we hypothesize that RasGRP1 participates in carcinogenesis by mediating biochemical Ras activation and cooperating with oncogenic Ras in tumor formation. In this application, we propose to identify the mechanisms of cooperation between Ras and RasGRP1 during skin carcinogenesis, both in the absence and presence of Ras oncogenic mutations. In addition, we plan to extend our observation in mouse models to a human model using the 3-D organotypic culture of human skin. The specific aims are: (1) Determine the mechanism of tumorigenesis induced by RasGRP1 in the absence of Ras oncogenic mutations: following findings from our recent studies on wounding-induced tumors in the RasGRP1 transgenic mice, we will focus on the potential role of cytokines and EGFR ligands in activation of the RasGRP1-Ras axis in the skin; (2) Investigate the cooperation between RasGRP1 and oncogenic Ras in tumor progression in the skin: our hypothesis is that RasGRP1 activates wild type Ras isoforms, particularly N-Ras, and cooperates with oncogenic Ras in tumor progression; and (3) Elucidate the role of RasGRP1 in human keratinocyte homeostasis and transformation: we will use human in vitro models to validate and understand the functions of RasGRP1 in carcinogenesis. The significance of the studies is that the identification of RasGRP1 as a relevant target in Ras modulation in carcinogenesis can be used to develop new interventions for chemoprevention and/or cancer therapy. Moreover, the findings derived from this proposal should also contribute to advance our understanding of Ras signaling pathways beyond skin carcinogenesis, and may have applications to other systems where RasGRP1 is also expressed. PUBLIC HEALTH RELEVANCE: The Ras proto-oncogene and its signaling pathways have been recognized to play a major role in human tumors; understanding the mechanisms governing these pathways may provide new molecular targets for therapeutic intervention in cancer. We have recently identified a novel Ras activator -RasGRP1- in the epidermal keratinocytes, which are the cells of origin of non-melanoma skin cancer. Using mouse models, we found that RasGRP1 participates in skin carcinogenesis. The studies we propose in this application will serve to identify the mechanisms of RasGRP1 tumorigenic effects. In addition, the results derived from the studies will contribute to our understanding of the control of Ras signaling pathways during tumor initiation, promotion and progression.

描述（由申请人提供）：皮肤癌发生的小鼠模型已用于研究肿瘤发生的多阶段性质，并鉴定新的癌基因和肿瘤抑制基因，以及与癌症相关的信号通路。在经典的两阶段致癌模型中，Ras 被致癌物诱导的突变激活，随后用佛波酯治疗会诱导肿瘤生长。然而，Ras 引发的细胞肿瘤形成机制以及佛波酯信号通路的参与仍知之甚少。使用小鼠皮肤模型，我们发现 RasGRP1 是皮肤癌发生的新型调节因子。 RasGRP1 连接佛波酯和 Ras，因为它既是高亲和力佛波酯受体又是 Ras 激活剂。使用转基因小鼠，我们证明 RasGRP1 通过野生型 Ras 的生化激活参与两阶段致癌模型中的肿瘤发生和进展。此外，表皮过度表达RasGRP1的转基因小鼠容易自发产生皮肤肿瘤。综上所述，我们假设 RasGRP1 通过介导生化 Ras 激活并与致癌 Ras 合作参与肿瘤形成，从而参与癌变。在此应用中，我们建议确定 Ras 和 RasGRP1 在皮肤癌发生过程中的合作机制，无论是否存在 Ras 致癌突变。此外，我们计划利用人类皮肤的 3D 器官培养将小鼠模型的观察扩展到人类模型。具体目标是：（1）确定RasGRP1在没有Ras致癌突变的情况下诱导肿瘤发生的机制：根据我们最近对RasGRP1转基因小鼠受伤诱发肿瘤的研究结果，我们将重点关注细胞因子的潜在作用和 EGFR 配体激活皮肤中的 RasGRP1-Ras 轴； (2)研究RasGRP1与致癌Ras在皮肤肿瘤进展中的协同作用：我们的假设是RasGRP1激活野生型Ras亚型，特别是N-Ras，并与致癌Ras协同参与肿瘤进展； (3)阐明RasGRP1在人类角质形成细胞稳态和转化中的作用：我们将利用人类体外模型来验证和了解RasGRP1在致癌作用中的功能。这些研究的意义在于，将 RasGRP1 确定为致癌过程中 Ras 调节的相关靶标，可用于开发化学预防和/或癌症治疗的新干预措施。此外，该提案的结果还应有助于增进我们对皮肤癌发生之外的 Ras 信号通路的理解，并可能应用于也表达 RasGRP1 的其他系统。公共健康相关性：Ras 原癌基因及其信号通路已被认为在人类肿瘤中发挥重要作用；了解控制这些途径的机制可能为癌症的治疗干预提供新的分子靶点。我们最近在表皮角质形成细胞中发现了一种新型 Ras 激活剂 -RasGRP1-，表皮角质形成细胞是非黑色素瘤皮肤癌的起源细胞。使用小鼠模型，我们发现 RasGRP1 参与皮肤癌发生。我们在本申请中提出的研究将有助于确定 RasGRP1 致瘤作用的机制。此外，研究结果将有助于我们了解肿瘤发生、促进和进展过程中 Ras 信号通路的控制。