Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
J Invest Dermatol. 2018 Mar;138(3):669-678. doi: 10.1016/j.jid.2017.10.007. Epub 2017 Dec 6.
Accumulating evidence has described the involvement of mTORC1 signaling in pigmentation regulation; however, the precise mechanism is not fully understood. Here, we generated mice with conditional deletion of the mTORC1 suppressor Tsc2 in melanocytes. It resulted in constitutive hyperactivation of mTORC1 and reduced skin pigmentation. Mechanistically, neither the number of melanocytes nor the expression of melanogenesis-related enzymes was decreased; however, endoplasmic reticulum and mitochondrial oxidative stress and lower melanization in melanosomes were observed. By contrast, abrogation of mTORC1 by rapamycin completely reversed the reduced pigmentation, and alleviation of endoplasmic reticulum stress by SMER28 or 4-phenylbutyrate (PBA) or alleviation of mitochondrial oxidative stress by administration of adenosine triphosphate partially reversed the reduced pigmentation in these mice. In addition, we showed that these mechanisms were involved in reduced pigmentation of TSC2 small interfering RNA-transfected cultured human primary melanocytes and skin lesions of patients with the TSC gene mutation.
越来越多的证据描述了 mTORC1 信号通路在色素沉着调控中的作用；然而，其确切机制尚不完全清楚。在这里，我们生成了黑素细胞中条件性缺失 mTORC1 抑制因子 Tsc2 的小鼠。结果导致 mTORC1 的持续过度激活和皮肤色素沉着减少。从机制上讲，黑素细胞的数量和黑色素生成相关酶的表达都没有减少；然而，内质网和线粒体的氧化应激以及黑色素体中的黑色素化程度降低。相比之下，雷帕霉素抑制 mTORC1 完全逆转了色素沉着减少，而用 SMER28 或 4-苯基丁酸（PBA）减轻内质网应激或用三磷酸腺苷（ATP）减轻线粒体氧化应激部分逆转了这些小鼠的色素沉着减少。此外，我们还表明，这些机制参与了 TSC2 小干扰 RNA 转染培养的人原代黑素细胞和 TSC 基因突变患者皮肤病变中的色素沉着减少。
