PUBLICATION

Minimal contribution of ERK1/2-MAPK signalling towards the maintenance of oncogenic GNAQQ209P-driven uveal melanomas in zebrafish

Authors
Mouti, M.A., Dee, C., Coupland, S.E., Hurlstone, A.F.
ID
ZDB-PUB-160512-6
Date
2016
Source
Oncotarget   7(26): 39654-39670 (Journal)
Registered Authors
Hurlstone, Adam
Keywords
ERK1/2, GNAQ, p53, uveal melanoma, zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Carcinogens
  • Cell Line
  • Cell Lineage
  • DNA Transposable Elements
  • Extracellular Signal-Regulated MAP Kinases/metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genes, p53
  • Humans
  • Immunohistochemistry
  • MAP Kinase Signaling System*
  • Melanocytes/metabolism
  • Mutation
  • Signal Transduction
  • Uveal Neoplasms/enzymology*
  • Uveal Neoplasms/genetics
  • Zebrafish
PubMed
27166257 Full text @ Oncotarget
Abstract
Mutations affecting Gαq proteins are pervasive in uveal melanoma (UM), suggesting they 'drive' UM pathogenesis. The ERK1/2-MAPK pathway is critical for cutaneous melanoma development and consequently an important therapeutic target. Defining the contribution of ERK1/2-MAPK signalling to UM development has been hampered by the lack of an informative animal model that spontaneously develops UM. Towards this end, we engineered transgenic zebrafish to express oncogenic GNAQQ209P in the melanocyte lineage. This resulted in hyperplasia of uveal melanocytes, but with no evidence of malignant progression, nor perturbation of skin melanocytes. Combining expression of oncogenic GNAQQ209P with p53 inactivation resulted in earlier onset and even more extensive hyperplasia of uveal melanocytes that progressed to UM. Immunohistochemistry revealed only weak immunoreactivity to phosphorylated (p)ERK1/2 in established uveal tumours-in contrast to strong immunoreactivity in oncogenic RAS-driven skin lesions-but ubiquitous positive staining for nuclear Yes-associated protein (YAP). Moreover, no changes were observed in pERK1/2 levels upon transient knockdown of GNAQ or phospholipase C-beta (PLC-β) inhibition in the majority of human UM cell lines we tested harbouring GNAQ mutations. In summary, our findings demonstrate a weak correlation between oncogenic GNAQQ209P mutation and sustained ERK1/2-MAPK activation, implying that ERK1/2 signalling is unlikely to be instrumental in the maintenance of GNAQQ209P-driven UMs.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping