PDZK1 upregulation in estrogen-related hyperpigmentation in melasma.
The pathogenesis of melasma is unknown, although the potential role of estrogen has been considered. Microarray and real-time PCR analyses revealed that upregulation of PDZ domain protein kidney 1 (PDZK1) is clinically correlated with melasma. Although there has been no report that PDZK1 is involved in pigmentation and/or melanogenesis, PDZK1 expression can be induced by estrogen. In this study, the role of PDZK1 upregulation in melasma was examined, particularly in connection with estrogen, using biopsied skin specimens from 15 patients and monocultures and cocultures of melanocytes and keratinocytes with or without overexpression or knockdown of PDZK1. Estrogen upregulated PDZK1. Overexpression of PDZK1 increased tyrosinase expression and melanosome transfer to keratinocytes, whereas PDZK1 knockdown reduced estrogen-induced tyrosinase expression, through regulation of expression of estrogen receptors (ERs) ER-α and ER-β. The PDZK1-induced tyrosinase expression and melanosome transfer was regulated by ion transporters such as sodium-hydrogen exchanger (NHE), cystic fibrosis transmembrane conductance regulator (CFTR), and SLC26A3, which showed a specific association with each ER subtype. In the melanosome transfer, PDZK1 also increased phosphorylation of ezrin/radixin/moesin (ERM) and ras-related C3 botulinum toxin substrate 1, but not the expression of proteinase-activated receptor-2. Collectively, upregulation of PDZK1 could have an important role in the development of melasma in connection with estrogen through NHE, CFTR, and SLC26A3.
Department of Dermatology, Dongguk University Ilsan Hospital, Goyang-si, Gyenggi-do, South Korea.
Nan-Hyung
NH
Kim
Kyung Ah
KA
Cheong
Tae Ryong
TR
Lee
Ai-Young
AY
Lee
D000328:Adult; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D000078404:Epidermal Cells; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D008548:Melanosis / Q000235:genetics* / Q000473:pathology*; D020460:Melanosomes / Q000378:metabolism; D008565:Membrane Proteins; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000076988:Sulfate Transporters; D015854:Up-Regulation / Q000502:physiology
C505032:CFTR protein, human; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D027963:Chloride-Bicarbonate Antiporters; D004967:Estrogens; D008565:Membrane Proteins; C484659:PDZK1 protein, human; C081011:SLC26A3 protein, human; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014442:Monophenol Monooxygenase