Downregulation of SIK2 expression promotes the melanogenic program in mice
Downregulation of SIK2 expression promotes the melanogenic program in mice
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DOI：
10.1111/j.1755-148x.2010.00760.x
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发表时间：
2010-12-01
影响因子：
4.3
通讯作者：
Takemori, Hiroshi
中科院分区：
文献类型：
--
作者：
Horike, Nanao;Kumagai, Ayako;Takemori, Hiroshi
cAMP反应元件结合蛋白（CREB）通过诱导小眼症相关转录因子（Mitf）基因表达促进黑素生成。我们在这里报告，CREB特异性辅激活TORC和它的阻遏物，盐诱导激酶2（SIK 2），是小鼠黑素生成程序的基本决定因素。B16黑色素瘤细胞暴露于紫外线（UV）光导致TORC 1立即核转位，这被SIK 2抑制。显性负性TORC 1的过表达也抑制UV诱导的Mitf基因表达和黑素生成。α-MSH信号传导调节毛发色素沉着，毛囊黑素细胞中α-MSH活性的降低将黑素合成从真黑素（黑色）转换为褐黑素（黄色）。具有致死性的agglutinin（Ay）黄色等位基因的小鼠由于α-MSH受体的活化受损而具有黄色毛发。为了研究SIK 2参与体内黑素生成开关的调节，我们制备了SIK 2敲除小鼠，并将Sik 2-/-基因型引入Ay/a小鼠。所得的Sik 2-/-; Ay/a小鼠具有棕色毛发，表明SIK 2抑制小鼠中的真黑素生成。
P>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. alpha-MSH signaling regulates hair pigmentation, and the decrease in alpha-MSH activity in hair follicle melanocytes switches the melanin synthesis from eumelanin (black) to pheomelanin (yellow). Mice with the lethal yellow allele of agouti (Ay) have yellow hair because of impaired activation of the alpha-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 Ay/a mice. The resultant Sik2-/-; Ay/a mice had brown hair, indicating that SIK2 represses eumelanogenesis in mice.