Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 11, Pages 4519-4524Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0900780106
Keywords
BRAF mutation; dual specificity phosphatase; mitogen-activated protein kinase, extracellular signal-regulated kinase kinase inhibition
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Funding
- National Institutes of Health
- William H. Goodwin and Alice Goodwin Foundation for Cancer Research
- Memorial Sloan-Kettering Cancer Center Experimental Therapeutics Program
- Starr Foundation
- Pfizer Oncology
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Tumors with mutant BRAF and those with receptor tyrosine kinase (RTK) activation have similar levels of phosphorylated ERK, but only the former depend on ERK signaling for proliferation. The mitogen-activated protein kinase, extracellular signal-regulated kinase kinase (MEK)/ERK-dependent transcriptional output was defined as the genes whose expression changes significantly 8 h after MEK inhibition. In (V600E)BRAF cells, this output is comprised of 52 genes, including transcription factors that regulate transformation and members of the dual specificity phosphatase and Sprouty gene families, feedback inhibitors of ERK signaling. No such genes were identified in RTK tumor cells, suggesting that ERK pathway signaling output is selectively activated in BRAF mutant tumors. We find that RAF signaling is feedback down-regulated in RTK cells, but is insensitive to this feedback in BRAF mutant tumors. Physiologic feedback inhibition of RAF/MEK signaling down-regulates ERK output in RTK cells; evasion of this feedback in mutant BRAF cells is associated with increased transcriptional output and MEK/ERK-dependent transformation.
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