Calcium -Inducible MAPK/AP-1 Signaling Drives Semaphorin 3A Expression in Normal Human Epidermal Keratinocytes
Calcium -Inducible MAPK/AP-1 Signaling Drives Semaphorin 3A Expression in Normal Human Epidermal Keratinocytes
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DOI：
10.1016/j.jid.2020.01.001
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发表时间：
2020-07-01
影响因子：
6.5
通讯作者：
Takamori, Kenji
中科院分区：
文献类型：
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作者：
Kamata, Yayoi;Tominaga, Mitsutoshi;Takamori, Kenji
表皮角质形成细胞主要参与脑信号蛋白（semaphorin，Sema）3A的表达，其参与皮肤神经支配的调节。然而，角质形成细胞中Sema 3A表达的细胞内信号转导机制仍不清楚。我们研究了正常人表皮角质形成细胞（NHEK）中Sema 3A表达的信号转导机制，结果发现，在钙离子刺激的NHEK中，Sema 3A表达短暂增加，而在终末分化的NHEK中，Sema 3A表达显著减少; Sema 3AmRNA主要定位于表皮的基底层和基底上层。我们克隆了Sema 3A基因的5 '侧翼区，并在起始密码子的-134碱基对内鉴定了Sema 3A启动子活性的关键区域。我们在该区域发现了转录因子结合位点，包括激活蛋白（AP）-1的结合位点。在0.1或1.4 mM钙的存在下，JunB和Fra-2的共同过表达增加了Sema 3A的表达。丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）激酶（MEK）1/2或AP-1抑制剂可显著抑制钙介导的Sema 3A表达的瞬时上调。这些结果表明，钙介导的NHEKs中Sema 3A的瞬时上调涉及MEK/ERK和AP-1信号传导轴。因此，Sema 3AmRNA可以在受控条件下通过MAPK-AP-1轴由钙在下表皮中表达。
Epidermal keratinocytes are primarily involved in the expression of semaphorin (Sema) 3A, which is involved in the regulation of cutaneous innervation. However, the mechanisms underlying the intracellular signaling ofSema3Aexpression in keratinocytes remain unknown. We herein investigated the signaling mechanisms for the induction ofSema3Aexpression in normal human epidermal keratinocytes (NHEKs).Sema3Aexpression is transiently increased in calcium-stimulated NHEKs, whereas it is markedly decreased in terminally differentiated NHEKs.Sema3AmRNA is mainly localized in the stratum basale and stratum suprabasale of the epidermis. We cloned the 5'-flanking region of theSema3Agene and identified a critical region forSema3Apromoter activity within -134 base pairs of the start codon. We found transcription factor binding sites, including that for activator protein (AP)-1, in this region.Sema3Aexpression was increased by the co-overexpression of JunB and Fra-2 in the presence of 0.1 or 1.4 mM calcium. The calcium-mediated transient upregulation ofSema3Aexpression was significantly suppressed by mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) kinase (MEK) 1/2 or AP-1 inhibitors. These results demonstrate that the calcium-mediated transient upregulation ofSema3Ain NHEKs is involved in the MEK/ERK and AP-1 signaling axis. Therefore,Sema3AmRNA may be expressed in the lower epidermis under controlled conditions by calcium via the MAPK–AP-1 axis.