Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 129, Issue 2, Pages 422-431Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jid.2008.255
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Funding
- Waltmar and Oxnard Foundations
- [CA62230]
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Microphthalmia-associated transcription factor (MiTF) is a key transcription factor for melanocyte lineage survival. Most previous work on this gene has been focused on its role in development. A role in carcinogenesis has emerged recently, but the mechanism is unclear. We classified melanoma cells into MiTF-positive and -negative groups and explored the function of MiTF in regulating cellular responses to reactive oxygen species (ROS). The MiTF-positive melanoma cell lines accumulated high levels of apurinic/apyrimidinic endonuclease (APE-1/Ref-1, redox effector-1), a key redox sensor and DNA endonuclease critical for oxidative DNA damage repair. We demonstrate that APE-1 is a transcriptional target for MiTF. Knocking down MiTF led to reduced APE-1 protein accumulation, as well as abolished induction of APE-1 by ROS. MiTF-negative melanoma cells survived more poorly under ROS stress than the MiTF-positive cells based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Trypan blue staining. Overexpression of APE-1 partially rescued ROS-induced cell death when MiTF was depleted. We conclude that MiTF regulates cellular response to ROS by regulation of APE-1, and this may provide a mechanism of how MiTF is involved in melanoma carcinogenesis.
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