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Regulation of tumor promotion by RasGRP1

RasGRP1 对肿瘤促进的调节

基本信息

批准号：
7437079
负责人：
PATRICIA S LORENZO
金额：
$ 6.85万
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 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7437079
关键词：
Address Affect Affinity Apoptosis Carcinogen exposure Carcinogens Cells Chemical Models Chemopreventive Agent Clonal Expansion Complement Data Development Diagnostic Neoplasm Staging Epidermis Epigenetic Process Esters Event Experimental Models Future Goals Growth HRAS gene Homeostasis Knock-out Knockout Mice Lead Link Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Target Mus Mutate Mutation Nature Oncogenic Pathway interactions Pharmaceutical Preparations Phorbol Esters Population Process Protein Kinase C Protein Overexpression Proteins Protocols documentation RAS genes Ras Signaling Pathway Regulation Role Signal Transduction Skin Skin Carcinogenesis Staging Testing Transgenic Animals Transgenic Mice Tumor Promoters Tumor Promotion Uncertainty Work base carcinogenesis chemical carcinogenesis in vivo Model keratinocyte novel phorbol ester receptor prototype receptors for activated C kinase response transmission process tumor

项目摘要

Tumor promotion is a reversible and non-genotoxic stage in carcinogenesis and, as a consequence, the various ! components of this process are central targets for the development of mechanism-based anticancer and[ chemopreventive drugs. In the mouse skin model of chemical-induced carcinogenesis, tumor promotion is achieved by] exposure of carcinogen-treated epidermis to phorbol esters, which induce the clonal expansion of those keratinocytes carrying the carcinogen-induced activating mutation in the H-Ras gene. The nature of the interaction between phorbol esters and Ras signaling in tumor promotion has not been defined yet. Although protein kinase C (PKC) has historically been considered responsible for all phorbol ester actions, the discovery of non-PKC receptors casts doubts on the assumption of an exclusive PKC-mediated effect. We have recently characterized the novel Ras activator RasGRP1 as a high affinity receptor for phorbol esters, and our preliminary data indicate that RasGRP1 is expressed in the epidermal keratinocyte, the target cell in chemical carcinogenesis. These data suggest that RasGRP1 may represent a novel and direct link between Ras and phorbol ester signaling in the epidermis. The present proposal will address this possibility. We hypothesize that phorbol esters can modulate RasGRP1 activity in keratinocytes, and that this modulation contributes to the mechanisms activated by tumor promotion during cancer formation. The specific aims to test the hypothesis are: (1) to define the functional role of RasGRP1 on the responses induced by phorbol esters in keratinocytes, including growth arrest, differentiation, and apoptosis; (2) to determine if RasGRP1 signaling is altered in initiated (H-Ras-mutated) keratinocytes, either by changes in the level of expression of RasGRP1, changes in substrate affinity, or both; and (3) to establish in vivo models to investigate the role of RasGRP1 in skin carcinogenesis and tumor promotion (knockout and transgenic animals for RasGRP1). Taken together, the results of this study have the potential to unravel a new molecular target for the transmission of phorbol ester-signals involved in carcinogenesis. This information could lead to future approaches for developing novel chemopreventive compounds targeted to tumor _romotion events.

肿瘤促进是癌变过程中一个可逆且无基因毒性的阶段。