Yin Kelvin, Sturm Richard A, Smith Aaron G
School of Biomedical Science, The University of Queensland, Brisbane, Qld, Australia.
Exp Dermatol. 2014 Jul;23(7):449-52. doi: 10.1111/exd.12420.
Ultraviolet radiation (UVR) is the most common mutagen that melanocytes are exposed to. UVR causes a diverse range of DNA photolesions contributing to genome instability and promotes melanoma and non-melanoma development. Melanocytes are pigment-producing cells that synthesise the photoprotective melanins when the melanocortin-1 receptor (MC1R) is activated. MC1R is a G-protein-coupled receptor expressed predominantly in melanocytes. Its signalling pathway has been directly linked to melanogenesis, enhanced cytoprotection against UV damage and augmented DNA repair response. Interestingly, previous studies have revealed that MC1R signalling induces the transcription of the NR4A subfamily of orphan nuclear receptors in response to UV. In line with this, studies have also observed that NR4A receptors are recruited to distinct nuclear foci in response to cellular stress, independent of their transcriptional roles. Here, we review the regulated expression of NR4A2 and its potential roles upon cellular stress conditions. Current work in developing synthetic NR4A2 agonists further provides exciting avenues for exploring the potential role of NR4A2 as an antiskin cancer drug target.
紫外线辐射（UVR）是黑素细胞所接触到的最常见诱变剂。UVR会导致多种DNA光损伤，造成基因组不稳定，并促进黑色素瘤和非黑色素瘤的发展。黑素细胞是产生色素的细胞，当黑素皮质素-1受体（MC1R）被激活时，它们会合成具有光保护作用的黑色素。MC1R是一种主要在黑素细胞中表达的G蛋白偶联受体。其信号通路已直接与黑色素生成、增强对紫外线损伤的细胞保护作用以及增强DNA修复反应相关联。有趣的是，先前的研究表明，MC1R信号传导会诱导孤儿核受体NR4A亚家族在紫外线作用下进行转录。与此一致的是，研究还观察到，NR4A受体在细胞应激反应中会被招募到不同的核灶中，这与其转录作用无关。在此，我们综述了NR4A2的调控表达及其在细胞应激条件下的潜在作用。目前在开发合成NR4A2激动剂方面的工作进一步为探索NR4A2作为抗皮肤癌药物靶点的潜在作用提供了令人兴奋的途径。
