Regulation of NR4A nuclear receptor expression by oncogenic BRAF in melanoma cells.

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.

• Authors: Aaron G Smith, Wen Lim, Michael Pearen, George E O Muscat, Richard A Sturm
• Journal: Pigment cell & melanoma research (Pigment Cell Melanoma Res) Vol. 24 Issue 3 Pg. 551-63 (Jun 2011) ISSN: 1755-148X [Electronic] England
• PMID: 21362156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2011 John Wiley & Sons A/S.

Chemical References

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• CITED1 protein, human
• DACT1 protein, human
• NR4A1 protein, human
• NR4A2 protein, human
• Nuclear Proteins
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Nuclear Receptor Subfamily 4, Group A, Member 2
• Trans-Activators
• Transcription Factors
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Apoptosis Regulatory Proteins
• COS Cells
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (genetics)
• Chlorocebus aethiops
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System
• Melanoma (genetics, metabolism, pathology)
• Mitogen-Activated Protein Kinase Kinases (genetics, metabolism)
• Mutation
• Neoplasm Invasiveness
• Nuclear Proteins (genetics, metabolism)
• Nuclear Receptor Subfamily 4, Group A, Member 1 (genetics, metabolism)
• Nuclear Receptor Subfamily 4, Group A, Member 2 (genetics, metabolism)
• Proto-Oncogene Proteins B-raf (biosynthesis, genetics)
• Trans-Activators
• Transcription Factors (genetics, metabolism)