机构：[1]Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA[2]Cutaneous Biology Research Center, MassachusettsGeneral Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA[3]Jinan University Institute of Tumor Pharmacology, Guangzhou, Guangdong 510632, China[4]Hunan KeyLaboratory of Skin Cancer and Psoriasis/Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China[5]Department of Dermatology, Xijing Hospital,The Fourth Military Medical University, Xi’an, Shaanxi 710000, China[6]Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin,300193, China[7]State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China[8]Division of Hematology and Oncology, Department ofMedicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA[9]Ludwig Institute for Cancer Research, University of Oxford, Headington,Oxford OX3 7DQ, UK
The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.
基金：
This work was supported by the National Institutes of Health
(R.C.: R01CA137098, R01CA193913 and R01CA196896), Department
of Defense (R.C., CA140020), Melanoma Research Foundation Establish
Investigator Award (R.C.), Hong Kong and Macao Young Scientists of the
National Natural Science Foundation of China (R.C., 81428025), National
Natural Science Foundation of China (X.G., 81630106), and the Ludwig
Institute for Cancer Research (C.R.G.). R.C. is an American Cancer Society
Research Scholar.
语种：
外文
PubmedID：
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第一作者：
第一作者机构：[1]Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA
共同第一作者：
推荐引用方式(GB/T 7714)：
Shuyang Chen,Bo Zhu,Chengqian Yin,et al.Palmitoylation-dependent activation of MC1R prevents melanomagenesis.[J].Nature.2017,549(7672):399-403.doi:10.1038/nature23887.
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