The Unfolded Protein Response Is Activated in Differentiating Epidermal Keratinocytes
The Unfolded Protein Response Is Activated in Differentiating Epidermal Keratinocytes
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DOI：
10.1038/jid.2009.51
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发表时间：
2009-09-01
影响因子：
6.5
通讯作者：
Usukura, Jiro
中科院分区：
文献类型：
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作者：
Sugiura, Kazumitsu;Muro, Yoshinao;Usukura, Jiro
未折叠蛋白反应（unfolded protein response，UPR）是由应激诱导的内质网反应，参与某些细胞的功能改变，如B细胞向浆细胞的分化。本研究的目的是确定UPR在表皮角质形成细胞（KC）分化过程中是否被激活。在这里，我们发现，在正常人表皮的基底层上的细胞中，UPR诱导的蛋白质Bip/GRP 78和HRD 1的表达增加，该细胞含有正在分化的KC，以及在皮肤等效培养的KC。然而，Bip/GRP 78和HRD 1在鳞状细胞癌和寻常型银屑病组织中增殖的KCs中表达较低。表皮生长因子受体酪氨酸激酶抑制剂PD 153035诱导KC分化，上调UPR诱导的标志物mRNA和蛋白质。此外，微阵列分析和定量PCR显示，ER应激诱导试剂，衣霉素（TU），毒胡萝卜素，和布雷菲德菌素A，改变了人类表皮KC分化所必需的基因的表达，包括C/EBP β，KLF 4，和ABCA 12在体外。然而，在siRNA介导的XBP-1敲低后，TU处理不会增加ABCA 12和KLF 4 mRNA。总之，我们的研究结果强烈表明，UPR在正常表皮KC分化过程中被激活，并诱导C/EBP β，KLF 4和ABCA 12 mRNA。
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.