Inhibition of JNK promotes differentiation of epidermal keratinocytes
Inhibition of JNK promotes differentiation of epidermal keratinocytes
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DOI：
10.1074/jbc.m602712200
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发表时间：
2006-07-21
影响因子：
4.8
通讯作者：
Blumenberg, Miroslav
中科院分区：
文献类型：
--
作者：
Gazel, Alix;Banno, Tomohiro;Blumenberg, Miroslav
在发炎的组织中，正常的信号转导途径被细胞外信号改变。例如，JNK通路在银屑病皮肤中被激活，这使其成为有吸引力的治疗靶点。为了全面定义JNK调控的基因在人表皮角质形成细胞，我们比较了控制和JNK通路处理角质形成细胞的转录谱，使用DNA微阵列。我们在SP 600125处理后1、4、24和48小时鉴定了差异表达的基因。令人惊讶的是，JNK在体外角质形成细胞培养物中的抑制诱导了体内表皮分化的几乎所有方面：角化标记物的转录、运动性的抑制、从细胞周期中退出、分层，甚至产生角质层包膜。JNK的抑制还诱导脂质和类固醇代谢的酶、二酰基甘油和磷酸肌醇途径的蛋白质、线粒体蛋白、组蛋白和DNA修复酶的产生，这些酶以前与分化无关。同时，基底细胞标志物，包括整合素，半桥粒和细胞外基质成分，被抑制。调控基因的启动子分析发现，叉头家族转录因子的结合位点在SP 600125诱导的基因和c-Fos位点的抑制基因中过度表达。JNK诱导的增殖似乎是继发于分化抑制。结果表明，抑制表皮角质形成细胞中的JNK足以启动其分化程序，并表明增强JNK活性可用于延迟角化和促进伤口愈合，而减弱JNK活性可能是治疗银屑病的基于分化疗法的方法。
In inflamed tissue, normal signal transduction pathways are altered by extracellular signals. For example, the JNK pathway is activated in psoriatic skin, which makes it an attractive target for treatment. To define comprehensively the JNK-regulated genes in human epidermal keratinocytes, we compared the transcriptional profiles of control and JNK inhibitor-treated keratinocytes, using DNA microarrays. We identified the differentially expressed genes 1, 4, 24, and 48 h after the treatment with SP600125. Surprisingly, the inhibition of JNK in keratinocyte cultures in vitro induces virtually all aspects of epidermal differentiation in vivo: transcription of cornification markers, inhibition of motility, withdrawal from the cell cycle, stratification, and even production of cornified envelopes. The inhibition of JNK also induces the production of enzymes of lipid and steroid metabolism, proteins of the diacylglycerol and inositol phosphate pathways, mitochondrial proteins, histones, and DNA repair enzymes, which have not been associated with differentiation previously. Simultaneously, basal cell markers, including integrins, hemidesmosome and extracellular matrix components, are suppressed. Promoter analysis of regulated genes finds that the binding sites for the forkhead family of transcription factors are over-represented in the SP600125-induced genes and c-Fos sites in the suppressed genes. The JNK-induced proliferation appears to be secondary to inhibition of differentiation. The results indicate that the inhibition of JNK in epidermal keratinocytes is sufficient to initiate their differentiation program and suggest that augmenting JNK activity could be used to delay cornification and enhance wound healing, whereas attenuating it could be a differentiation therapy-based approach for treating psoriasis.