FOXO1 promotes wound healing through the up-regulation of TGF-β1 and prevention of oxidative stress.
FOXO1 promotes wound healing through the up-regulation of TGF-β1 and prevention of oxidative stress.
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DOI：
10.1083/jcb.201305074
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发表时间：
2013-10-28
期刊：
影响因子：
--
通讯作者：
Graves DT
中科院分区：
文献类型：
--
作者：
Ponugoti B;Xu F;Zhang C;Tian C;Pacios S;Graves DT
FOXO1通过上调TGF-β1和抗氧化应激调控创面愈合，共同促进角质细胞迁移，减少细胞凋亡。角化细胞的动员是伤口再上皮化的一个关键方面，但控制其精确调节的机制仍然知之甚少。我们开始验证叉头盒O1 （FOXO1）对愈合有负面影响的假设，因为它具有抑制增殖和促进细胞凋亡的能力。与预期相反，FOXO1是角质细胞向伤口愈合表型转变所必需的，该表型涉及转化生长因子β1 （TGF-β1）及其下游靶点整合素-α3和-β6以及MMP-3和-9的迁移增加和上调。此外，我们发现FOXO1在角质形成细胞中减少氧化应激，这是维持细胞迁移和防止细胞死亡所必需的，不依赖于TGF-β1。因此，我们的研究发现FOXO1通过上调TGF-β1等角化细胞迁移和氧化应激保护所需的因子，共同促进迁移和减少凋亡，从而协调角化细胞对损伤的反应。
FOXO1 orchestrates wound healing through the up-regulation of TGF-β1 and protection against oxidative stress, which together act to promote keratinocyte migration and decrease apoptosis. Keratinocyte mobilization is a critical aspect of wound re-epithelialization, but the mechanisms that control its precise regulation remain poorly understood. We set out to test the hypothesis that forkhead box O1 (FOXO1) has a negative effect on healing because of its capacity to inhibit proliferation and promote apoptosis. Contrary to expectations, FOXO1 is required for keratinocyte transition to a wound-healing phenotype that involves increased migration and up-regulation of transforming growth factor β1 (TGF-β1) and its downstream targets, integrin-α3 and -β6 and MMP-3 and -9. Furthermore, we show that FOXO1 functions in keratinocytes to reduce oxidative stress, which is necessary to maintain cell migration and prevent cell death in a TGF-β1–independent manner. Thus, our studies identify a novel function for FOXO1 in coordinating the response of keratinocytes to wounding through up-regulation of TGF-β1 and other factors needed for keratinocyte migration and protection against oxidative stress, which together promote migration and decrease apoptosis.
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