Downregulation of SIK2 expression promotes the melanogenic program in mice.
cAMP response element-binding protein (CREB) promotes melanogenesis by inducing microphthalmia-associated transcription factor (Mitf ) gene expression. We report here that the CREB-specific coactivator TORC and its repressor, salt-inducible kinase 2 (SIK2), are fundamental determinants of the melanogenic program in mice. Exposure of B16 melanoma cells to ultraviolet (UV) light results in the immediate nuclear translocation of TORC1, which is inhibited by SIK2. Overexpression of dominant-negative TORC1 also inhibits UV-induced Mitf gene expression and melanogenesis. α-MSH signaling regulates hair pigmentation, and the decrease in α-MSH activity in hair follicle melanocytes switches the melanin synthesis from eumelanin (black) to pheomelanin (yellow). Mice with the lethal yellow allele of agouti (A(y)) have yellow hair because of impaired activation of the α-MSH receptor. To examine the involvement of SIK2 in the regulation of the melanogenesis switch in vivo, we prepared SIK2-knockout mice, and the Sik2(-/-) genotype was introduced into A(y)/a mice. The resultant Sik2(-/-); A(y)/a mice had brown hair, indicating that SIK2 represses eumelanogenesis in mice.
Horike
Nanao
N
Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito, Ibaraki, Osaka, Japan.
Kumagai
Ayako
A
Shimono
Yuko
Y
Onishi
Tomoko
T
Itoh
Yumi
Y
Sasaki
Tsutomu
T
Kitagawa
Kazuo
K
Hatano
Osamu
O
Takagi
Hiroaki
H
Susumu
Teruo
T
Teraoka
Hiroshi
H
Kusano
Ken-ichi
K
Nagaoka
Yasuo
Y
Kawahara
Hidehisa
H
Takemori
Hiroshi
H
D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics* / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006197:Hair; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis*; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D010858:Pigmentation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000378:metabolism
D007527:Isoenzymes; D008543:Melanins; D014157:Transcription Factors; D000521:alpha-MSH; D000242:Cyclic AMP; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases