Slc7a11 gene controls production of pheomelanin pigment and proliferation of cultured cells.
In mammals, >100 genes regulate pigmentation by means of a wide variety of developmental, cellular, and enzymatic mechanisms. Nevertheless, genes that directly regulate pheomelanin production have not been described. Here, we demonstrate that the subtle gray (sut) mouse pigmentation mutant arose by means of a mutation in the Slc7a11 gene, encoding the plasma membrane cystine/glutamate exchanger xCT [Kanai, Y. & Endou, H. (2001) Curr. Drug Metab. 2, 339-354]. A resulting low rate of extracellular cystine transport into sut melanocytes reduces pheomelanin production. We show that Slc7a11 is a major genetic regulator of pheomelanin pigment in hair and melanocytes, with minimal or no effects on eumelanin. Furthermore, transport of cystine by xCT is critical for normal proliferation, glutathione production, and protection from oxidative stress in cultured cells. Thus, we have found that the Slc7a11 gene controls the production of pheomelanin pigment directly. Cells from sut mice provide a model for oxidative stress-related diseases and their therapies.
Chintala
Sreenivasulu
S
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Li
Wei
W
Lamoreux
M Lynn
ML
Ito
Shosuke
S
Wakamatsu
Kazumasa
K
Sviderskaya
Elena V
EV
Bennett
Dorothy C
DC
Park
Young-Mee
YM
Gahl
William A
WA
Huizing
Marjan
M
Spritz
Richard A
RA
Ben
Songtao
S
Novak
Edward K
EK
Tan
Jian
J
Swank
Richard T
RT
D027182:Amino Acid Transport System y+ / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D049109:Cell Proliferation; D002478:Cells, Cultured; D002874:Chromosome Mapping; D003553:Cystine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018384:Oxidative Stress; D012880:Skin Pigmentation / Q000235:genetics / Q000502:physiology
D027182:Amino Acid Transport System y+; D008543:Melanins; C492255:Slc7a11 protein, mouse; C018362:pheomelanin; D003553:Cystine; D005978:Glutathione