Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1/2, p38, and phosphatidylinositol 3-kinase signaling pathways
Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1/2, p38, and phosphatidylinositol 3-kinase signaling pathways
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DOI：
10.1074/jbc.m606094200
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发表时间：
2007-05-18
影响因子：
4.8
通讯作者：
Ponzio, Gilles
中科院分区：
文献类型：
--
作者：
Fitsialos, Giorgos;Chassot, Anne-Amandine;Ponzio, Gilles
在损伤后覆盖裸露的真皮表面需要皮肤角质形成细胞的迁移、增殖和分化。为了阐明控制这些混杂的生物学事件的主要性状，我们调查了培养的人角质形成细胞的划痕伤口闭合过程中发生的基因组修饰。使用DNA微阵列的方法，我们报告了161个新的表皮修复标志物的鉴定。表达数据，结合与ERK，p38（MAPK）和磷脂酰肌醇3-激酶（PI 3 K）的特异性抑制剂进行的功能分析，表明激酶途径发挥非常有选择性的功能，通过精确控制特定基因的表达。ERK通路的抑制完全阻断伤口闭合并使许多早期转录因子和EGF型生长因子失活。p38（MAPK）抑制仅延迟“愈合”，这可能与参与损伤引发的信号传导的传播的基因的控制一致。相反，PI 3 K抑制加速划痕闭合，并增强与上皮细胞转化相关的三个基因（即HAS 3、HBEGF和ETS 1）的划痕依赖性刺激。我们的研究结果定义在体外人角质形成细胞伤口闭合作为一个修复过程，导致从ERK和p38（MAPK）和负PI 3 K触发的信号之间的良好平衡控制的正信号。任何这些途径的扰动可能导致愈合过程中的功能障碍，类似于在病理性创伤表型中观察到的那些，如增生性瘢痕或瘢痕疙瘩。
Covering denuded dermal surfaces after injury requires migration, proliferation, and differentiation of skin keratinocytes. To clarify the major traits controlling these intermingled biological events, we surveyed the genomic modifications occurring during the course of a scratch wound closure of cultured human keratinocytes. Using a DNA microarray approach, we report the identification of 161 new markers of epidermal repair. Expression data, combined with functional analysis performed with specific inhibitors of ERK, p38(MAPK) and phosphatidylinositol 3-kinase ( PI3K), demonstrate that kinase pathways exert very selective functions by precisely controlling the expression of specific genes. Inhibition of the ERK pathway totally blocks the wound closure and inactivates many early transcription factors and EGF-type growth factors. p38(MAPK) inhibition only delays "healing," probably in line with the control of genes involved in the propagation of injury-initiated signaling. In contrast, PI3K inhibition accelerates the scratch closure and potentiates the scratch-dependent stimulation of three genes related to epithelial cell transformation, namely HAS3, HBEGF, and ETS1. Our results define in vitro human keratinocyte wound closure as a repair process resulting from a fine balance between positive signals controlled by ERK and p38(MAPK) and negative ones triggered by PI3K. The perturbation of any of these pathways might lead to dysfunction in the healing process, similar to those observed in pathological wounding phenotypes, such as hypertrophic scars or keloids.