Kazumitsu Sugiura, Yoshinao Muro, Kyoko Futamura, Kenji Matsumoto, Noriko Hashimoto, Yuji Nishizawa, Tetsuro Nagasaka, Hirohisa Saito, Yasushi Tomita, Jiro Usukura
JOURNAL OF INVESTIGATIVE DERMATOLOGY 129(9) 2126-2135 2009年9月 査読有り筆頭著者責任著者
The unfolded protein response (UPR), which is induced by stress to the endoplasmic reticulum (ER), is involved in the functional alteration of certain cells, such as the differentiation of B cells to plasma cells. The aim of this study is to determine whether the UPR is activated during epidermal keratinocyte (KC) differentiation. Here, we show that the expression of the UPR-induced proteins Bip/GRP78 and HRD1 was increased in cells in the suprabasal layers of normal human epidermis that contain KCs undergoing differentiation as well as in skin-equivalent cultured KCs. However, Bip/GRP78 and HRD1 were poorly expressed in proliferating KCs in squamous cell carcinoma and psoriasis vulgaris tissues. The epidermal growth factor receptor tyrosine kinase inhibitor, PD153035, which induces KC differentiation, upregulated UPR-induced marker mRNAs and proteins. Furthermore, microarray analyses and quantitative PCR revealed that ER stress-inducing reagents, tunicamycin (TU), thapsigargin, and brefeldin A, altered the expression of genes essential for human epidermal KC differentiation, including C/EBP beta, KLF4, and ABCA12 in vitro. However, ABCA12 and KLF4 mRNA did not increase with TU treatment after siRNA-mediated knockdown of XBP-1. Taken together, our findings strongly suggest that the UPR is activated during normal epidermal KC differentiation and induces C/EBP beta, KLF4, and ABCA12 mRNAs.