ATP2C1 is specifically localized in the basal layer of normal epidermis and its depletion triggers keratinocyte differentiation

Summary Background ATP2C1 is a calcium/manganese-ATPase localized in the Golgi apparatus and known as responsible gene for Hailey–Hailey disease. But its localization and roles in the epidermis are not fully elucidated. Objective To explore the localization and biological role of ATP2C1 in normal epidermis in terms of differentiation states. Methods We examined the immunohistochemical distribution of ATP2C1 in normal epidermis and measured the expression of ATP2C1 in cultured keratinocytes following forced detachment from culture dish or following treatment with high concentrations of calcium. Furthermore, we knockdown ATP2C1 expression in cultured keratinocytes by using RNA interference procedure to abrogate cation accumulation in cell organelles. Results ATP2C1 is specifically localized at the basal cell layer in normal epidermis. Neither detachment of keratinocyte from culture dish nor treatment with high concentrations of calcium suppressed ATP2C1 expression, while both procedures induced differentiation markers, K10 keratin and involucrin. In contrast, knockdown of ATP2C1 induced these differentiation markers of cultured keratinocytes. Furthermore, treatment of keratinocytes with a calcium ionophore, A23187, did not up-regulate differentiation markers of keratinocytes, while a more manganese selective ionophore Br-A23187 up-regulated these differentiation markers. Conclusion Our results suggest that ATP2C1 plays an essential role for basal keratinocytes to keep in the undifferentiated state and that its reduction evokes differentiation and up-localization to suprabasal layers most likely via the manganese starvation in the Golgi apparatus of keratinocytes.