Regulation of tumor promotion by RasGRP1

RasGRP1 对肿瘤促进的调节

基本信息

批准号：
8497786
负责人：
PATRICIA S LORENZO
金额：
$ 3.27万
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/8497786
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.

描述（由申请人提供）：皮肤致癌的小鼠模型已有助于研究肿瘤发生的多阶段性质，并鉴定出新的癌基因和肿瘤抑制基因，以及在癌症中相关的信号通路。在经典的两阶段癌变模型中，RAS被致癌诱导的突变激活，随后用佛波酯进行治疗会诱导肿瘤促进。但是，导致RAS引发的细胞形成的机制以及佛波酯信号通路的参与仍然很少了解。使用小鼠皮肤模型，我们将RASGRP1确定为皮肤致癌作用的新型调节剂。 RASGRP1将佛波酯和RAS连接起来，因为它既是高亲和力phorbol酯受体和RAS激活剂。使用转基因小鼠，我们表明RASGRP1通过野生型Ras的生化激活参与了两阶段致癌模型的肿瘤起始和进展。此外，表皮中过表达RASGRP1的转基因小鼠容易自发发展皮肤肿瘤。综上所述，我们假设RASGRP1通过介导生化RAS激活并与肿瘤形成中的致癌性RAS合作，参与致癌。在此应用中，我们建议在不存在RAS致癌突变的情况下，在皮肤致癌过程中确定RAS和RASGRP1之间的合作机制。此外，我们计划使用人类皮肤的3-D器官培养物将小鼠模型中的观察结果扩展到人类模型。 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）研究皮肤肿瘤进展中RASGRP1与致癌性RA之间的合作：我们的假设是RasGRP1激活了野生型Ras同工型，尤其是N-RAS，尤其是N-RAS，以及与肿瘤进展中的致癌Ras合作；（3）阐明RASGRP1在人角质形成细胞稳态和转化中的作用：我们将使用人类体外模型来验证和理解RasGRP1在致癌作用中的功能。研究的意义在于，在癌变中，将RASGRP1鉴定为RAS调节中的相关靶标，可用于开发用于化学预防和/或癌症治疗的新干预措施。此外，从该提案中得出的发现也应有助于提高我们对RAS信号通路的理解，而不是皮肤致癌，并且可能在其他表达RASGRP1的系统中应用。