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Review
. 2014 Dec 1:563:28-34.
doi: 10.1016/j.abb.2014.07.019. Epub 2014 Aug 9.

The roles of microphthalmia-associated transcription factor and pigmentation in melanoma

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Review

The roles of microphthalmia-associated transcription factor and pigmentation in melanoma

Jennifer J Hsiao et al. Arch Biochem Biophys. .

Abstract

MITF and pigmentation play important roles in both normal melanocyte and transformed melanoma cell biology. MITF is regulated by many pathways and it also regulates many _targets, some of which are still being discovered and functionally validated. MITF is involved in a wide range of processes in melanocytes, including pigment synthesis and lineage survival. Pigmentation itself plays an important role as the interface between genetic and environmental factors that contribute to melanoma.

Keywords: MITF; Melanocyte; Melanoma; Pigmentation.

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Figures

Figure 1
Figure 1. Regulators of MITF
The regulation of MITF is complex, with multiple upstream pathways converging on MITF. The pathways thought to be relevant to both normal melanocytes and transformed melanoma cells include the tanning pathway, the MAPK pathway, and the PI3K pathway. PAX3, SOX10, PGC1, LEF, and CREB are some of the known transcription factors that bind to the MITF promoter and regulate its transcription. AC = adenylate cyclase.
Figure 2
Figure 2. MITF _targets
MITF is the master regulator of the melanocyte. Its many _targets include those involved in a wide range of pathways that are relevant to both normal melanocytes and melanoma cells.
Figure 3
Figure 3. The tanning pathway (top) and melanin synthesis pathway (bottom)
The physiologic skin pigmentation response (tanning) begins with exposure to UV radiation, which causes DNA damage and thus upregulates p53, leading to POMC transcription in keratinocytes. POMC is enzymatically cleaved to produce αMSH, which binds to MC1R on melanocytes. This triggers the rest of the tanning response, ultimately resulting in transcription of MITF and its _targets, which include the pigmentation enzymes tyrosinase, DCT, and TYRP1. Melanin is produced in melanosomes and transported to keratinocytes, where they form protective caps over the keratinocyte nuclei. Synthesis of both types of melanins (bottom) begins with the amino acid tyrosine. Tyrosinase catalyzes the rate-limiting step for both eumelanin and pheomelanin. Eumelanin synthesis additionally requires the enzymes DCT and TYRP1, while pheomelanin additionally requires the amino acid cysteine.

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