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Cell Rep ; 22(9): 2455-2468, 2018 02 27.
Article in English | MEDLINE | ID: mdl-29490280

ABSTRACT

Uveal melanoma (UM) is characterized by mutually exclusive activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4, four genes in a linear pathway to activation of PLCß in almost all tumors and loss of BAP1 in the aggressive subset. We generated mice with melanocyte-specific expression of GNA11Q209L with and without homozygous Bap1 loss. The GNA11Q209L mice recapitulated human Gq-associated melanomas, and they developed pigmented neoplastic lesions from melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as at atypical sites, including the lymph nodes and lungs. The addition of Bap1 loss increased tumor proliferation and cutaneous melanoma size. Integrative transcriptome analysis of human and murine melanomas identified RasGRP3 to be specifically expressed in GNAQ/GNA11-driven melanomas. In human UM cell lines and murine models, RasGRP3 is specifically required for GNAQ/GNA11-driven Ras activation and tumorigenesis. This implicates RasGRP3 as a critical node and a potential target in UM.


Subject(s)
GTP-Binding Protein alpha Subunits/metabolism , Melanocytes/metabolism , Melanoma/metabolism , Melanoma/pathology , Signal Transduction , Uveal Neoplasms/metabolism , Uveal Neoplasms/pathology , ras Guanine Nucleotide Exchange Factors/metabolism , Animals , Cell Line, Tumor , Cell Lineage/drug effects , Cell Proliferation/drug effects , Central Nervous System Neoplasms/pathology , Disease Models, Animal , Female , Humans , Male , Melanocytes/drug effects , Melanocytes/pathology , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Invasiveness , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Skin Neoplasms/pathology , Tumor Suppressor Proteins/metabolism , Ubiquitin Thiolesterase/metabolism
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