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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF
Claudia Wellbrock1, Sareena Rana, Hugh Paterson
1Signal Transduction Team, The Institute of Cancer Research, Cancer Research UK Centre of Cell and Molecular Biology, London, United Kingdom.
Plos One
|July 17, 2008
Summary
Oncogenic BRAF in melanoma paradoxically controls Microphthalmia-associated transcription factor (MITF) by both degrading its protein and upregulating its transcription via BRN2, ensuring melanoma cell survival and proliferation.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Microphthalmia-associated transcription factor (MITF) regulates melanocytic cell functions, with high levels promoting differentiation and lower levels supporting melanoma cell survival.
- ERK-mediated phosphorylation of MITF stimulates activation but also targets it for proteasomal degradation.
- Mutated BRAF in melanoma leads to hyper-activated ERK, causing constitutive downregulation of MITF protein.
Purpose of the Study:
- To investigate the novel regulatory mechanisms of MITF by oncogenic BRAF in melanoma cells.
- To elucidate the dual role of oncogenic BRAF in controlling MITF protein levels.
- To understand how MITF contributes to melanoma cell proliferation and survival downstream of BRAF.
Main Methods:
- Analysis of MITF regulation in melanoma cells versus melanocytes.
- Investigating the role of ERK and BRN2 in MITF transcription.
- Examining the downstream targets of MITF, including cell cycle regulators like CDK2 and CDK4.
Main Results:
- Oncogenic BRAF upregulates MITF transcription through ERK and BRN2, a pathway absent in melanocytes.
- MITF is essential downstream of oncogenic BRAF, regulating key cell cycle proteins (CDK2, CDK4) for melanoma proliferation.
- Oncogenic BRAF simultaneously downregulates MITF protein via degradation and upregulates its transcription, maintaining levels compatible with melanoma survival.
Conclusions:
- Oncogenic BRAF exerts dual control over MITF in melanoma, balancing protein degradation with transcriptional upregulation.
- This appropriated regulation of MITF by oncogenic BRAF is a critical adaptation for melanoma cell proliferation and survival.
- The intricate control of MITF by BRAF highlights its potent oncogenic activity in melanoma.
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