A potent inhibitor of SIK2, 3, 3', 7-trihydroxy-4'-methoxyflavon (4'-O-methylfisetin), promotes melanogenesis in B16F10 melanoma cells.
A potent inhibitor of SIK2, 3, 3', 7-trihydroxy-4'-methoxyflavon (4'-O-methylfisetin), promotes melanogenesis in B16F10 melanoma cells.
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DOI：
10.1371/journal.pone.0026148
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nagaoka Y
中科院分区：
文献类型：
--
作者：
Kumagai A;Horike N;Satoh Y;Uebi T;Sasaki T;Itoh Y;Hirata Y;Uchio-Yamada K;Kitagawa K;Uesato S;Kawahara H;Takemori H;Nagaoka Y
类黄酮是一种植物多酚，现在被广泛用于补充剂和化妆品中。在这里，我们报告了4‘-甲基黄酮类化合物是B16F10黑色素瘤细胞和小鼠黑色素瘤黑素合成的有效诱导剂。我们最近发现盐诱导蛋白2(SIK2)是通过抑制cAMP反应元件结合蛋白(CREB)特异性辅活化子1(TORC1)而抑制黑素合成的。使用针对SIK2的体外激酶试验，我们确定Fisetin是一个候选抑制物，可能能够促进黑素合成。然而，Fisetin既不抑制SIK2的CREB抑制活性，也不促进B16F10黑色素瘤细胞的黑素合成。相反，单甲基黄酮类化合物，如Diosmetin(4‘-O-甲基木犀草素)，有效地抑制SIK2并促进该细胞系的黑素合成。在Ay/a小鼠中，cAMP-CREB系统受损，这些小鼠因皮肤病发生而出现黄毛，而SIK2+/−；Ay/a小鼠也有黄发，但当它们暴露于CREB刺激剂时，激活了真黑素的生成。给SIK2+/−；Ay/a小鼠饲喂添加鱼腥草素的饲料后，它们的毛发颜色变为棕色，代谢物分析表明它们的粪便中存在单甲基鱼腥草素。因此，我们决定合成4‘-O-甲基菲斯汀(4’-MF)，发现4‘-MF强烈诱导B16F10黑色素瘤细胞的黑素生成，并伴随着TORC1的核转位，而4’-O-甲基非瑟素诱导的黑素生成程序被显性负性TORC1的过表达所抑制。总之，调节SIK2级联反应的化合物有助于在不影响cAMP水平的情况下通过TORC1来调节黑素合成，联合分析SIK2+/−小鼠和这些小鼠的代谢物是寻找在体内调节CREB活性的有益化合物的有效策略。
Flavonoids, which are plant polyphenols, are now widely used in supplements and cosmetics. Here, we report that 4′-methylflavonoids are potent inducers of melanogenesis in B16F10 melanoma cells and in mice. We recently identified salt inducible kinase 2 (SIK2) as an inhibitor of melanogenesis via the suppression of the cAMP-response element binding protein (CREB)-specific coactivator 1 (TORC1). Using an in vitro kinase assay targeting SIK2, we identified fisetin as a candidate inhibitor, possibly being capable of promoting melanogenesis. However, fisetin neither inhibited the CREB-inhibitory activity of SIK2 nor promoted melanogenesis in B16F10 melanoma cells. Conversely, mono-methyl-flavonoids, such as diosmetin (4′-O-metlylluteolin), efficiently inhibited SIK2 and promoted melanogenesis in this cell line. The cAMP-CREB system is impaired in Ay/a mice and these mice have yellow hair as a result of pheomelanogenesis, while Sik2+/−; Ay/a mice also have yellow hair, but activate eumelanogenesis when they are exposed to CREB stimulators. Feeding Sik2+/−; Ay/a mice with diets supplemented with fisetin resulted in their hair color changing to brown, and metabolite analysis suggested the presence of mono-methylfisetin in their feces. Thus, we decided to synthesize 4′-O-methylfisetin (4′MF) and found that 4′MF strongly induced melanogenesis in B16F10 melanoma cells, which was accompanied by the nuclear translocation of TORC1, and the 4′-O-methylfisetin-induced melanogenic programs were inhibited by the overexpression of dominant negative TORC1. In conclusion, compounds that modulate SIK2 cascades are helpful to regulate melanogenesis via TORC1 without affecting cAMP levels, and the combined analysis of Sik2+/− mice and metabolites from these mice is an effective strategy to identify beneficial compounds to regulate CREB activity in vivo.
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影响因子：
82.9
作者：
Altarejos, Judith Y.;Goebel, Naomi;Conkright, Michael D.;Inotiel, Hiroshi;Xie, Jianxin;Arias, Carlos M.;Sawchenko, Paul E.;Montminy, Marc
通讯作者：
Montminy, Marc
影响因子：
4.8
作者：
Liu, Ying;Coello, Ana G.;Aguilera, Greti
通讯作者：
Aguilera, Greti
影响因子：
5.4
作者：
Katoh, Yoshiko;Takemori, Hiroshi;Okamoto, Mitsuhiro
通讯作者：
Okamoto, Mitsuhiro
影响因子：
6.1
作者：
Lee, Jongsung;Jung, Kwangseon;Park, Deokhoon
通讯作者：
Park, Deokhoon
DOI：
10.1073/pnas.0607822103
发表时间：
2006-10-31
影响因子：
11.1
作者：
Maher, Pamela;Akaishi, Tatsuhiro;Abe, Kazuho
通讯作者：
Abe, Kazuho