title: PGC-1 coactivators regulate MITF and the tanning response.
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.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shoag
authors.forename: Rizwan
authors.initials: R
authors.lastname: Haq
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhang
authors.forename: Laura
authors.initials: L
authors.lastname: Liu
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.forename: Aihua
authors.initials: A
authors.lastname: Jiang
authors.forename: Nicole
authors.initials: N
authors.lastname: Koulisis
authors.forename: Caitlin
authors.initials: C
authors.lastname: Farrel
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.forename: Abrar A
authors.initials: AA
authors.lastname: Qureshi
authors.forename: Rutao
authors.initials: R
authors.lastname: Cui
authors.forename: Jiali
authors.initials: J
authors.lastname: Han
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000201:enzymology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014442:Monophenol Monooxygenase / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D016601:RNA-Binding Proteins; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055107:Suntan / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D000521:alpha-MSH / Q000378:metabolism / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D006360:Heat-Shock Proteins; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000521:alpha-MSH; D014442:Monophenol Monooxygenase