Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the Sp1, CREB, AP1, and AP2 families
Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the Sp1, CREB, AP1, and AP2 families
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DOI：
10.1074/jbc.m205593200
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发表时间：
2002-11-01
影响因子：
4.8
通讯作者：
Steinert, PM
中科院分区：
文献类型：
--
作者：
Jang, SI;Steinert, PM
表皮的角质形成细胞包膜屏障结构的主要蛋白质组分是兜甲蛋白，并且其在表皮角质形成细胞的终末分化期间晚期表达。我们先前已经表明，位于近端启动子区（位置-55）的AP 1位点对于人兜甲蛋白启动子活性是必需的（Rossi，A.，Jang，S-I.，塞西河Steinert，P.M.，和Markova，N. G.（1998）J. Invest. Dermatol 110，34-40）。在这项研究中，我们表明，它的调节需要复杂的合作和竞争之间的相互作用，在角质形成细胞位于表皮的不同隔间的多种转录因子。我们发现，从帽位点的5 '上游序列的少至154个碱基对可以指导培养的角质形成细胞中的角质形成细胞特异性表达。突变和DNA-蛋白质分析表明，Sp1，c-Jun，一种未鉴定的调节剂，和共激活剂p300/CREB结合蛋白上调，而Sp3，CREB-1/CREMalpha/ATF-1，Jun B，和AP 2样蛋白（称为角质形成细胞特异性阻遏物-1（KSR-1））抑制兜甲蛋白启动子活性。我们发现CREB蛋白可以与c-Jun竞争AP 1位点并抑制兜甲蛋白启动子活性。我们在这里表明，蛋白激酶A途径可以激活兜甲蛋白的表达操纵的Sp1，Sp3和KSR-1的水平在细胞核中。因此，在未分化的细胞中，兜甲蛋白的表达受到Jun B、Sp3和KSR-1蛋白的抑制。但在晚期分化的细胞中，Sp3、KSR-1和CREB蛋白的水平较低;未鉴定的调节蛋白可以结合; Sp1和c-Jun增加;然后招募p300/CBP。这些事件一起允许兜甲蛋白转录进行。事实上，Sp1，c-Jun和p300因子的协同作用表明，p300/CBP可能作为桥梁，形成一个活跃的转录复合物。
The major protein component of the cornified cell envelope barrier structure of the epidermis is loricrin, and it is expressed late during terminal differentiation in epidermal keratinocytes. We have previously shown that an AP1 site located in the proximal promoter region (position -55) is essential for human loricrin promoter activity (Rossi, A., Jang, S-I., Ceci, R., Steinert, P. M., and Markova, N. G. (1998) J. Invest. Dermatol 110, 34-40). In this study we show that its regulation requires complex cooperative and competitive interactions between multiple transcription factors in keratinocytes located in different compartments of the epidermis. We show that as few as 154 base pairs of 5'-upstream sequences from the cap site can direct the keratinocyte-specific expression in cultured keratinocytes. Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. We show that CREB protein can compete with c-Jun for the AP1 site and repress loricrin promoter activity. We show here that the protein kinase A pathway can activate loricrin expression by manipulation of the Sp1, Sp3, and KSR-1 levels in the nucleus. Thus, in undifferentiated cells, loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. But in advanced differentiated cells, levels of Sp3, KSR-1, and CREB proteins are lower; the unidentified regulator protein can bind; Sp1 and c-Jun are increased; and then p300/CBP is recruited. Together, these events allow loricrin transcription to proceed. Indeed, the synergistic effects of the Sp1, c-Jun, and p300 factors indicate that p300/CBP might act as bridge to form an active transcription complex.