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Regulation of ERK3/MAPK6 expression by BRAF
Klaus P Hoeflich1, Michael T Eby, William F Forrest
1Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
International Journal of Oncology
|September 12, 2006
Summary
Activating BRAF mutations drive cancer. This study identifies novel genes regulated by BRAF signaling, including extracellular signal-regulated kinase-3 (ERK3), a potential marker for BRAF-targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating mutations in the serine/threonine kinase BRAF, particularly the BRAF V600E mutation, are common in various cancers.
- These mutations lead to increased kinase activity, aberrant downstream signaling, and cellular transformation, driving oncogenesis.
Purpose of the Study:
- To comprehensively analyze the transcriptional program regulated by oncogenic BRAF signaling.
- To identify novel genes involved in BRAF-mediated oncogenesis.
- To investigate the role of extracellular signal-regulated kinase-3 (ERK3/MAPK6) in BRAF-driven signaling.
Main Methods:
- Microarray gene expression profiling of cells with conditionally active BRAF V600E.
- Analysis of novel gene expression changes.
- Investigation of ERK3 protein stability and regulation.
- RNA interference (RNAi) mediated knockdown of BRAF and MEK inhibitor treatment in melanoma cells.
Main Results:
- Identified novel genes influencing proliferation, cell survival, angiogenesis, and immune surveillance as mediators of BRAF oncogenic signaling.
- Demonstrated high expression of extracellular signal-regulated kinase-3 (ERK3/MAPK6) in response to BRAF signaling.
- Showed that BRAF inhibition leads to rapid ERK3 degradation.
- Confirmed that elevated ERK3 expression is mediated through MEK1/2 signaling in melanoma cells.
Conclusions:
- BRAF signaling regulates a distinct transcriptional program involving novel oncogenic mediators.
- Extracellular signal-regulated kinase-3 (ERK3) is a novel downstream target of BRAF/MEK signaling.
- ERK3 represents a potential pharmacodynamic marker for monitoring BRAF-targeted therapies in melanoma.
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