Abstract
Activating mutations in the MAPK pathway effectors, NRAS or BRAF, are detected in over 70% of melanomas. Accordingly, the identification of downstream targets of constitutive MAPK signalling in melanoma represents a major goal in understanding the genesis of this disease. We report here the regulation of members of the NR4A family of nuclear receptors by the BRAF-MEK-ERK cascade in melanoma cells. Expression profiling of melanoma cells in which both the NR4A1 and NR4A2 family members have been down-regulated by siRNA revealed alterations in genes associated with proliferation, survival and invasiveness of tumour cells. Notably, the up-regulation of Wnt/β-catenin pathway antagonists, DACT1 and CITED1, following NR4A1/2 ablation suggests a possible link between NR4A and β-catenin activity in melanoma cells. Taken together, these data suggest that dysregulation of NR4A nuclear receptors expression and function by the MAPK pathway may contribute to melanoma tumourigenicity.
2011 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis Regulatory Proteins
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COS Cells
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival / genetics
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Chlorocebus aethiops
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Humans
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MAP Kinase Signaling System*
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Melanoma / genetics
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Melanoma / metabolism*
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Melanoma / pathology
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mutation
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Neoplasm Invasiveness
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
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Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
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Proto-Oncogene Proteins B-raf / biosynthesis*
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Proto-Oncogene Proteins B-raf / genetics
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Trans-Activators
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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CITED1 protein, human
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DACT1 protein, human
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NR4A1 protein, human
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NR4A2 protein, human
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Nuclear Proteins
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Nuclear Receptor Subfamily 4, Group A, Member 2
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Trans-Activators
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Transcription Factors
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Kinases