Transcriptional profiling defines the roles of ERK and p38 kinases in epidermal keratinocytes
Transcriptional profiling defines the roles of ERK and p38 kinases in epidermal keratinocytes
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DOI：
10.1002/jcp.21394
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发表时间：
2008-05-01
影响因子：
5.6
通讯作者：
Blumenberg, Miroslav
中科院分区：
文献类型：
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作者：
Gazel, Alix;Nijhawan, Rajiv I.;Blumenberg, Miroslav
表皮角质形成细胞通过激活改变基因表达的细胞质信号转导途径对细胞外影响作出反应。使用通路特异性转录谱分析，我们确定了两个这样的途径，p38和ERK调控的基因。这些途径是表皮分化、增殖性和炎性皮肤病的支点。我们使用SB 203580和PD 98059作为特异性抑制剂，使用AffyphidHu 133 Av 2微阵列，鉴定1、4、24和48 h后调控的基因，并将其与JNK调控的基因进行比较。出乎意料的是，MAPK途径的抑制通过NF κ B途径的激活和DUSP酶的抑制来补偿。这两种途径都促进表皮分化;然而，类固醇合成酶和分化标志物的表达之间存在令人惊讶的脱节。p38通路诱导细胞外基质和增殖相关基因的表达，同时抑制微管相关基因。ERK途径诱导核膜和mRNA剪接蛋白，同时抑制类固醇合成和线粒体能量产生酶。转录因子SRY、c-FOS和N-Myc是p38通路、ERK的Elk-I SAPI和HLH 2的主要靶标，而FREAC-4、ARNT和USF是共享的。结果提出了一系列可能用于皮肤疾病和伤口愈合治疗干预的靶点。
Epidermal keratinocytes respond to extracellular influences by activating cytoplasmic signal transduction pathways that change gene expression. Using pathway-specific transcriptional profiling, we identified the genes regulated by two such pathways, p38 and ERK. These pathways are at the fulcrum of epidermal differentiation, proliferative and inflammatory skin diseases. We used SB203580 and PD98059 as specific inhibitors and Affymetrix Hu 133Av2 microarrays, to identify the genes regulated after 1, 4, 24, and 48 h and compared them to genes regulated by JNK. Unexpectedly, inhibition of MAPK pathways is compensated by activation of the NF kappa B pathway and suppression of the DUSP enzymes. Both pathways promote epidermal differentiation; however, there is a surprising disconnect between the expression of steroid synthesis enzymes and differentiation markers. The p38 pathway induces the expression of extracellular matrix and proliferation-associated genes, while suppressing microtubule-associated genes. The ERK pathway induces nuclear envelope and mRNA splicing proteins, while suppressing steroid synthesis and mitochondrial energy production enzymes. Transcription factors SRY, c-FOS, and N-Myc are the principal targets of the p38 pathway, Elk-I SAPI and HLH2 of ERK, while FREAC-4, ARNT and USF are shared. The results suggest a list of targets potentially useful in therapeutic interventions in cutaneous diseases and wound healing.