Extra-Nuclear Functions of the Transcription Factor Grainyhead-Like 3 in the Endothelium-Interaction with Endothelial Nitric Oxide Synthase.
Extra-Nuclear Functions of the Transcription Factor Grainyhead-Like 3 in the Endothelium-Interaction with Endothelial Nitric Oxide Synthase.
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DOI：
10.3390/antiox10030428
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发表时间：
2021-03-11
期刊：
影响因子：
--
通讯作者：
Altschmied J
中科院分区：
文献类型：
--
作者：
Jander K;Greulich J;Gonnissen S;Ale-Agha N;Goy C;Jakobs P;Farrokh S;Marziano C;Sonkusare SK;Haendeler J;Altschmied J
我们以前证明，转录因子Grainyhead样3（GRHL3）在内皮细胞中具有重要的功能，通过抑制凋亡和促进迁移以及激活内皮型一氧化氮合酶（eNOS）。我们现在表明，大部分的蛋白质是本地化的小鼠动脉肌内皮细胞的预测表明核外功能。因此，我们产生了各种缺失突变体，以确定核定位信号（NLS）的GRHL 3和评估潜在的核外功能。几个大规模的缺失突变体不能激活GRHL 3依赖的报告构建体，这可能是由于转录激活或受损的核输入的缺陷。其中一个突变体包含一个预测的二分NLS，其缺失导致GRHL 3保留在细胞核外。有趣的是，这种突变体保留了全长蛋白的功能，因为它仍然可以抑制诱导内皮细胞凋亡的途径。由于GRHL3的凋亡保护依赖于NO的产生，我们研究了GRHL3是否可以与eNOS相互作用，并显示出直接的相互作用，这是增强与核外GRHL3变体。内源性GRHL3也与eNOS在完整的小鼠动脉中相互作用的观察结果证实了这些发现，并证实了GRHL3在内皮细胞中具有重要的核外功能的概念。
We previously demonstrated that the transcription factor Grainyhead-like 3 (GRHL3) has essential functions in endothelial cells by inhibiting apoptosis and promoting migration as well as activation of endothelial nitric oxide synthase (eNOS). We now show that a large portion of the protein is localized to myo-endothelial projections of murine arteries suggesting extra-nuclear functions. Therefore, we generated various deletion mutants to identify the nuclear localization signal (NLS) of GRHL3 and assessed potential extra-nuclear functions. Several large-scale deletion mutants were incapable of activating a GRHL3-dependent reporter construct, which could either be due to deficiencies in transcriptional activation or to impaired nuclear import. One of these mutants encompassed a predicted bipartite NLS whose deletion led to the retention of GRHL3 outside the nucleus. Interestingly, this mutant retained functions of the full-length protein as it could still inhibit pathways inducing endothelial cell apoptosis. As apoptosis protection by GRHL3 depends on NO-production, we examined whether GRHL3 could interact with eNOS and showed a direct interaction, which was enhanced with the extra-nuclear GRHL3 variant. The observation that endogenous GRHL3 also interacts with eNOS in intact murine arteries corroborated these findings and substantiated the notion that GRHL3 has important extra-nuclear functions in the endothelium.
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影响因子：
4.1
作者：
Ting, SB;Wilanowski, T;Jane, SM
通讯作者：
Jane, SM
影响因子：
56.9
作者：
Ting, SB;Caddy, J;Jane, SM
通讯作者：
Jane, SM
DOI：
10.1016/j.bbrc.2011.08.018
发表时间：
2011-09-09
影响因子：
3.1
作者：
Lukosz, Margarete;Mlynek, Arne;Haendeler, Judith
通讯作者：
Haendeler, Judith
影响因子：
82.9
作者：
Ting, SB;Wilanowski, T;Jane, SM
通讯作者：
Jane, SM
影响因子：
64.8
作者：
Green, Douglas R.;Kroemer, Guido
通讯作者：
Kroemer, Guido