Department of Dermatology, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, South Korea.
Bioscience Research Division, R&D Unit, AmorePacific Corporation, Yongin, Gyeonggi-do, South Korea.
Pigment Cell Melanoma Res. 2017 Jan;30(6):521-530. doi: 10.1111/pcmr.12605. Epub 2017 Jul 23.
Expression profiles revealed miR-1299 downregulation concomitant with arginase-2 (ARG2) upregulation in hyperpigmented skin of melasma patients. Opposite regulation of tyrosinase and PMEL17 by miR-1299 and inverse relationship between miR-1299 and ARG2 expression denoted a role of miR-1299 in pigmentation with ARG2 as a miR-1299 target. ARG2 overexpression or knock-down in keratinocytes, the main source of ARG2 in epidermis, positively regulated tyrosinase and PMEL17 protein levels, but not mRNA levels or melanosome transfer. ARG2 overexpression in keratinocytes reduced autophagy equivalent to 3-MA, an autophagy inhibitor which also increased tyrosinase and PMEL17 protein levels, whereas ARG2 knock-down induced opposite results. Autophagy inducer rapamycin reduced ARG2-increased tyrosinase and PMEL17 protein levels. Also, autophagy was reduced in late passage-induced senescent keratinocytes showing ARG2 upregulation. ARG2, but not 3-MA, stimulated keratinocyte senescence. These results suggest that ARG2 reduces autophagy in keratinocytes by stimulating cellular senescence, resulting in skin pigmentation by reducing degradation of transferred melanosomes.
miR-1299 的表达谱显示在黄褐斑患者的色素沉着皮肤中下调，同时伴随着精氨酸酶-2（ARG2）的上调。miR-1299 对酪氨酸酶和 PMEL17 的相反调节作用以及 miR-1299 与 ARG2 表达之间的反比关系表明 miR-1299 在色素沉着中起作用，ARG2 是 miR-1299 的靶标。ARG2 在角质形成细胞中的过表达或敲低，角质形成细胞是表皮中 ARG2 的主要来源，可正向调节酪氨酸酶和 PMEL17 蛋白水平，但不调节 mRNA 水平或黑素体转移。角质形成细胞中 ARG2 的过表达相当于自噬抑制剂 3-MA，可降低自噬水平，同时也增加了酪氨酸酶和 PMEL17 蛋白水平，而 ARG2 的敲低则诱导了相反的结果。自噬诱导剂雷帕霉素降低了 ARG2 增加的酪氨酸酶和 PMEL17 蛋白水平。此外，晚期传代诱导衰老的角质形成细胞中自噬减少，同时显示 ARG2 的上调。ARG2 而不是 3-MA 刺激角质形成细胞衰老。这些结果表明，ARG2 通过刺激细胞衰老来降低角质形成细胞中的自噬，从而通过减少转移黑素体的降解导致皮肤色素沉着。
