title: G protein-coupled estrogen receptor enhances melanogenesis via cAMP-protein kinase (PKA) by upregulating microphthalmia-related transcription factor-tyrosinase in melanoma.
abstract: This study investigated the role and mechanism of action of G protein-coupled estrogen receptor (GPER) in melanogenesis.
  
  
  
  GPER expression was detected in the A375 human melanoma cell line and B16 mouse melanoma cell line. Cell proliferation, melanin content, tyrosinase (TYR) activity, cyclic adenosine monophosphate (cAMP) level, and TYR and microphthalmia-related transcription factor (MITF) expression were measured. GPER activation was altered by agonist and antagonist treatment and its expression was downregulated by gene silencing. Estradiol-induced melanin synthesis and the activation of related signaling pathways were suppressed by inhibiting GPER via antagonist treatment. The relationship between GPER and TYR was evaluated in clinical chloasma samples by immunohistochemistry.
  
  
  
  Upregulation of GPER in A375 cells promoted melanogenesis, favored as indicated by increases in TYR and MITF expression and TYR activity. GPER activated melanin production via the cAMP-protein kinase (PK) A pathway, suggesting that GPER plays an important role in estrogen-induced melanin synthesis. The effect of GPER activation on cAMP-MITF-TYR signaling was also demonstrated in B16 cells. A significant association was observed between GPER and TYR expression in chloasma skin lesions relative to normal skin.
  
  
  
  GPER enhances melanin synthesis via cAMP-PKA-MITF-TYR signaling and modulates the effects of estrogen in melanogenesis. GPER is therefore a potential drug target for chloasma treatment.
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Hong-Fu
authors.initials: HF
authors.lastname: Xie
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Shang-Qing
authors.initials: SQ
authors.lastname: Lin
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Jin-Mao
authors.initials: JM
authors.lastname: Li
authors.affiliation: Shangdong University of TCM, Shangdong, China.
authors.forename: Shu-Na
authors.initials: SN
authors.lastname: Sun
authors.affiliation: Department of Dermatology, First People's Hospital of Chenzhou City, Chenzhou, Hunan, China.
authors.forename: Xing-Lin
authors.initials: XL
authors.lastname: Hu
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Ying-Xue
authors.initials: YX
authors.lastname: Huang
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China. Electronic address: 569085332@qq.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Jian
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental; D008548:Melanosis / Q000188:drug therapy; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D010858:Pigmentation; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C109584:GPER1 protein, human; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Estrogen; G protein-coupled estrogen receptor (GPER/GPR30); Melanogenesis; Microphthalmia-related transcription factor (MITF); Tyrosinase