Abstract
Abstract The RAS effector RIN1 is frequently overexpressed in melanoma tumor samples. This aberrant overexpression is associated with tumor thickness, lymph node metastasis and poor prognosis. RIN1 is a multifunctional protein that has been shown to regulate growth factor receptor signaling and endocytosis, as well as the activity of the non-receptor tyrosine kinase ABL, which functions in actin remodeling and the DNA damage response. Here, we identify RIN1 as a suppressor of apoptosis in melanoma. shRNA-mediated knockdown of RIN1 in the melanoma cell line A375 suppressed proliferation and induced apoptosis. We found RIN1 to be commonly overexpressed in melanomas, with elevated levels of the protein detected in 10 of 13 melanoma cell lines tested in comparison with human neonatal melanocytes. Additionally, depletion of RIN1 in several primary cell types does not affect cell viability. This supports the hypothesis that some melanoma cells are addicted to RIN1 and suggests its potential as a therapeutic target. To examine the role of RIN1 in melanoma cell survival, point mutations were made to disrupt several known functions. These include receptor tyrosine kinase binding, ABL binding, Rab5 GEF activity and RAS association. The mutants have been stably transduced into melanoma cells under the control of a tetracycline-responsive promoter and they will be used to elucidate the contribution of different RIN1-dependent pathways to oncogenic activity. Overall, our goal is to determine the molecular mechanisms governing oncogenic addiction to RIN1 as well as points of vulnerability that could be therapeutically targeted. Citation Format: Pamela Y. Ting, John Colicelli. RIN1 suppresses apoptosis in melanoma cells and is a potential therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5197. doi:10.1158/1538-7445.AM2013-5197
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