V600EBRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway Journal Article
| Authors: | Pratilas, C. A.; Taylor, B. S.; Ye, Q.; Viale, A.; Sander, C.; Solit, D. B.; Rosen, N. |
| Article Title: | V600EBRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway |
| Abstract: | 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 <sup>V600E</sup>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. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; human cell; genetics; missense mutation; mutation, missense; raf protein; nonhuman; mutant protein; mouse; animal; metabolism; animals; mice; gene expression; gene expression profiling; animal experiment; animal model; down-regulation; transcription factor; genetic transcription; transcription, genetic; enzyme activation; enzyme activity; physiology; carcinogenesis; oncogene; gene identification; tyrosine kinase receptor; tumor cell; extracellular signal-regulated map kinases; down regulation; feedback system; negative feedback; b raf kinase; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; raf kinases; proto-oncogene proteins b-raf; braf mutation; dual specificity phosphatase; extracellular signal-regulated kinase kinase inhibition; mitogen-activated protein kinase; sprouty protein; braf protein, mouse; feedback, biochemical |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 106 |
| Issue: | 11 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2009-03-17 |
| Start Page: | 4519 |
| End Page: | 4524 |
| Language: | English |
| DOI: | 10.1073/pnas.0900780106 |
| PUBMED: | 19251651 |
| PROVIDER: | scopus |
| PMCID: | PMC2649208 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 34" - "Export Date: 30 November 2010" - "CODEN: PNASA" - "Source: Scopus" |
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