TAZ as a novel regulator of oxidative damage in decidualization via Nrf2/ARE/Foxo1 pathway.
TAZ as a novel regulator of oxidative damage in decidualization via Nrf2/ARE/Foxo1 pathway.
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TAZ 通过 Nrf2/ARE/Foxo1 途径作为蜕膜化氧化损伤的新型调节剂
DOI：
10.1038/s12276-021-00655-2
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发表时间：
2021-09
影响因子：
12.8
通讯作者：
Guo B
中科院分区：
文献类型：
--
作者：
Yu HF;Zheng LW;Yang ZQ;Wang YS;Wang TT;Yue ZP;Guo B
TAZ作为Hippo通路的重要效应子，在精子发生和受精过程中起重要作用，但其在子宫蜕膜化中的生理功能尚不清楚。在这项研究中，我们发现，TAZ是本地化的蜕膜，在那里它促进基质细胞增殖，然后通过Ccnd3和Cdk4加速G1/S期转变，并诱导基质分化标志物Prl8a2，Prl3c1和ALP的表达或活性，表明TAZ在蜕膜化中的重要性。TAZ的敲低阻碍了HB-EGF对基质细胞增殖和分化的诱导。在氧化应激下，TAZ通过减少细胞内ROS和增强依赖于Nrf2/ARE/Foxo1通路的细胞抗氧化能力来保护基质分化免受氧化损伤。TAZ能增强Nrf2的转录活性，Nrf2与Foxo1启动子区的抗氧化反应元件（ARE）直接结合。此外，沉默TAZ通过提高NOX活性引起细胞内ROS的积累，NOX活性被APO阻断逆转了基质分化的破坏。进一步分析表明，TAZ可能恢复线粒体功能，如ATP水平，线粒体DNA拷贝数和线粒体膜电位的增加，线粒体超氧化物的减少。此外，TAZ调制线粒体呼吸链复合物I和III的活动，其抑制ROT和AA导致TAZ无法抵御氧化损伤基质分化。TAZ通过上调Bcl 2表达、抑制Caspase 3活性和Bax表达，抑制基质细胞凋亡。TAZ可能通过Ccnd3介导HB-EGF在子宫蜕膜化中的作用，并通过Nrf2/ARE/Foxo1途径减轻氧化损伤对间质细胞分化的影响。
TAZ, as a crucial effector of Hippo pathway, is required for spermatogenesis and fertilization, but little is known regarding its physiological function in uterine decidualization. In this study, we showed that TAZ was localized in the decidua, where it promoted stromal cell proliferation followed by accelerated G1/S phase transition via Ccnd3 and Cdk4 and induced the expression or activity of stromal differentiation markers Prl8a2, Prl3c1 and ALP, indicating the importance of TAZ in decidualization. Knockdown of TAZ impeded HB-EGF induction of stromal cell proliferation and differentiation. Under oxidative stress, TAZ protected stromal differentiation against oxidative damage by reducing intracellular ROS and enhancing cellular antioxidant capacity dependent on the Nrf2/ARE/Foxo1 pathway. TAZ strengthened the transcriptional activity of Nrf2 which directly bound to the antioxidant response element (ARE) of Foxo1 promoter region. Additionally, silencing TAZ caused accumulation of intracellular ROS through heightening NOX activity whose blockade by APO reversed the disruption in stromal differentiation. Further analysis revealed that TAZ might restore mitochondrial function, as indicated by the increase in ATP level, mtDNA copy number and mitochondrial membrane potential with the reduction in mitochondrial superoxide. Additionally, TAZ modulated the activities of mitochondrial respiratory chain complexes I and III whose suppression by ROT and AA resulted in the inability of TAZ to defend against oxidative damage to stromal differentiation. Moreover, TAZ prevented stromal cell apoptosis by upregulating Bcl2 expression and inhibiting Casp3 activity and Bax expression. In summary, TAZ might mediate HB-EGF function in uterine decidualization through Ccnd3 and ameliorate oxidative damage to stromal cell differentiation via Nrf2/ARE/Foxo1 pathway.
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DOI：
10.1186/1477-7827-10-49
发表时间：
2012-06-29
期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
--
作者：
Agarwal A;Aponte-Mellado A;Premkumar BJ;Shaman A;Gupta S
通讯作者：
Gupta S
DOI：
10.1073/pnas.0605266104
发表时间：
2007-01-30
影响因子：
11.1
作者：
Hossain, Zakir;Ali, Safiah Mohamed;Hunziker, Walter
通讯作者：
Hunziker, Walter
影响因子：
3.6
作者：
Strakova, Zuzana;Reed, Jennifer;Ihnatovych, Ivanna
通讯作者：
Ihnatovych, Ivanna
影响因子：
56.9
作者：
Hong, JH;Hwang, ES;Yaffe, MB
通讯作者：
Yaffe, MB
影响因子：
4.8
作者：
Kim, A. Rum;Park, Jung Il;Hong, Jeong-Ho
通讯作者：
Hong, Jeong-Ho