Deng Maoxian, Chen Wei-Li, Takatori Atsushi, Peng Zhimin, Zhang Lin, Mongan Maureen, Parthasarathy Ranjani, Sartor Maureen, Miller Marian, Yang Jianhua, Su Bing, Kao Winston W-Y, Xia Ying
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Mol Biol Cell. 2006 Aug;17(8):3446-55. doi: 10.1091/mbc.e06-02-0102. Epub 2006 Jun 7.
The mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1) mediates activin B signals required for eyelid epithelium morphogenesis during mouse fetal development. The present study investigates the role of MEKK1 in epithelial wound healing, another activin-regulated biological process. In a skin wound model, injury markedly stimulates MEKK1 expression and activity, which are in turn required for the expression of genes involved in extracellular matrix (ECM) homeostasis. MEKK1 ablation or down-regulation by interfering RNA significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor (PAI)-1, and restoration of cell-cell junctions of the wounded epidermis. Conversely, expression of wild-type MEKK1 accelerates reepithelialization of full-thickness skin and corneal debridement wounds by mechanisms involving epithelial cell migration, a cell function that is partially abolished by neutralizing antibodies for PAI-1 and metalloproteinase III. Our data suggest that MEKK1 transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization.
丝裂原活化蛋白激酶激酶（MEK）激酶1（MEKK1）介导小鼠胎儿发育期间眼睑上皮形态发生所需的激活素B信号。本研究探讨MEKK1在另一种激活素调节的生物学过程——上皮伤口愈合中的作用。在皮肤伤口模型中，损伤显著刺激MEKK1的表达和活性，而MEKK1的表达和活性又是细胞外基质（ECM）稳态相关基因表达所必需的。通过干扰RNA对MEKK1进行基因敲除或下调，可显著延迟皮肤伤口愈合，并损害Jun NH2末端激酶的激活、纤溶酶原激活物抑制剂（PAI）-1的诱导以及受损表皮细胞间连接的恢复。相反，野生型MEKK1的表达通过涉及上皮细胞迁移的机制加速全层皮肤和角膜清创伤口的再上皮化，而PAI-1和金属蛋白酶III的中和抗体可部分消除上皮细胞迁移这种细胞功能。我们的数据表明，MEKK1传递伤口信号，导致参与ECM稳态、上皮细胞迁移和伤口再上皮化的基因发生转录激活。
