Abstract
The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete α-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-γ coactivator (PGC)-1α and PGC-1β are critical components of this melanogenic system in melanocytes. α-MSH signaling strongly induces PGC-1α expression and stabilizes both PGC-1α and PGC-1β proteins. The PGC-1s in turn activate the MITF promoter, and their expression correlates strongly with that of MITF in human melanoma cell lines and biopsy specimens. Inhibition of PGC-1α and PGC-1β blocks the α-MSH-mediated induction of MITF and melanogenic genes. Conversely, overexpression of PGC-1α induces pigment formation in cell culture and transgenic animals. Finally, polymorphism studies reveal expression quantitative trait loci in the PGC-1β gene that correlate with tanning ability and protection from melanoma in humans. These data identify PGC-1 coactivators as regulators of human tanning.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Case-Control Studies
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Cell Line, Tumor
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Gene Expression
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Genetic Association Studies
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Genetic Predisposition to Disease
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Heat-Shock Proteins / physiology*
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Humans
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Keratinocytes / metabolism
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Keratinocytes / radiation effects
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Melanins / biosynthesis
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Melanocytes / enzymology
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Melanocytes / metabolism
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Melanoma / genetics
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Melanoma / metabolism*
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Melanoma / pathology
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Mice
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Mice, Inbred C57BL
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Microphthalmia-Associated Transcription Factor / genetics
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Microphthalmia-Associated Transcription Factor / metabolism*
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Monophenol Monooxygenase / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Polymorphism, Single Nucleotide
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Promoter Regions, Genetic
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Protein Stability
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RNA-Binding Proteins
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism*
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Skin Neoplasms / pathology
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Suntan / genetics*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcriptional Activation
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alpha-MSH / metabolism
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alpha-MSH / physiology
Substances
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Carrier Proteins
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Heat-Shock Proteins
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MITF protein, human
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Melanins
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Microphthalmia-Associated Transcription Factor
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PPARGC1A protein, human
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PPARGC1B protein, human
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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RNA-Binding Proteins
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Transcription Factors
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alpha-MSH
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Monophenol Monooxygenase