title: Downregulation of SIK2 expression promotes the melanogenic program in mice.
abstract: 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.
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito, Ibaraki, Osaka, Japan.
authors.forename: Nanao
authors.initials: N
authors.lastname: Horike
authors.forename: Ayako
authors.initials: A
authors.lastname: Kumagai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimono
authors.forename: Tomoko
authors.initials: T
authors.lastname: Onishi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Itoh
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Hatano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takagi
authors.forename: Teruo
authors.initials: T
authors.lastname: Susumu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Teraoka
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kusano
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Nagaoka
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Kawahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
mesh_terms: 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
chemical_list: D007527:Isoenzymes; D008543:Melanins; D014157:Transcription Factors; D000521:alpha-MSH; D000242:Cyclic AMP; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases