Identification of direct transcriptional targets of V600EBRAF/MEK signalling in melanoma
Packer, Leisl M., East, Philip, Reis-Filho, Jorge S., & Marais, Richard (2009) Identification of direct transcriptional targets of V600EBRAF/MEK signalling in melanoma. Pigment Cell & Melanoma Research, 22(6), pp. 785-798.
Oncogenic mutations in BRAF are common in melanoma and drive constitutive activation of the MEK/ERK pathway. To elucidate the transcriptional events downstream of V600EBRAF/MEK signalling we performed gene expression profiling of A375 melanoma cells treated with potent and selective inhibitors of V600EBRAF 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 V600EBRAF/MEK signalling in melanoma cells.
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|Item Type:||Journal Article|
|Keywords:||2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; B Raf kinase; mitogen activated protein kinase; mitogen activated protein kinase inhibitor; plx 4720; unclassified drug; article; controlled study; down regulation; enzyme inhibition;|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL BIOCHEMISTRY AND METABOLOMICS (110100)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Deposited On:||23 Sep 2014 22:58|
|Last Modified:||24 Sep 2014 23:13|
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