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Identification of direct transcriptional targets of V600E BRAF/MEK signalling in melanoma
Author(s) -
Packer Leisl M,
East Philip,
ReisFilho Jorge S,
Marais Richard
Publication year - 2009
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2009.00618.x
Subject(s) - neuroblastoma ras viral oncogene homolog , melanoma , mapk/erk pathway , mek inhibitor , v600e , microphthalmia associated transcription factor , cancer research , hedgehog signaling pathway , rna interference , biology , gene expression profiling , transcription (linguistics) , gene , signal transduction , gene expression , transcription factor , mutant , microbiology and biotechnology , rna , mutation , genetics , kras , linguistics , philosophy
Summary Oncogenic mutations in BRAF are common in melanoma and drive constitutive activation of the MEK/ERK pathway. To elucidate the transcriptional events downstream of V600E BRAF/MEK signalling we performed gene expression profiling of A375 melanoma cells treated with potent and selective inhibitors of V600E BRAF and MEK (PLX4720 and PD184352 respectively). Using a stringent Bayesian approach, we identified 69 transcripts that appear to be direct transcriptional targets of this pathway and whose expression changed after 6 h of pathway inhibition. We also identified several additional genes whose expression changed after 24 h of pathway inhibition and which are likely to be indirect transcriptional targets of the pathway. Several of these were confirmed by demonstrating their expression to be similarly regulated when BRAF was depleted using RNA interference, and by using qRT‐PCR in other BRAF mutated melanoma lines. Many of these genes are transcription factors and feedback inhibitors of the ERK pathway and are also regulated by MEK signalling in NRAS mutant cells. This study provides a basis for understanding the molecular processes that are regulated by V600E BRAF/MEK signalling in melanoma cells.