García-Mariscal Alberto, Peyrollier Karine, Basse Astrid, Pedersen Esben, Rühl Ralph, van Hengel Jolanda, Brakebusch Cord
a Department of Biomedical Sciences , BRIC, University of Copenhagen , Copenhagen , Denmark.
b Laboratory of Nutritional Bioactivation and Bioanalysis, Research Center of Molecular Medicine, University of Debrecen , Hungary.
Small GTPases. 2018 Sep 3;9(5):433-444. doi: 10.1080/21541248.2016.1248272. Epub 2016 Nov 16.
The ubiquitously expressed small GTPase RhoA is essential for embryonic development and mutated in different cancers. Functionally, it is well described as a regulator of the actin cytoskeleton, but its role in gene regulation is less understood. Using primary mouse keratinocytes with a deletion of the RhoA gene, we have now been exploring how the loss of RhoA affects gene expression. Performing transcription factor reporter assays, we found a significantly decreased activity of a RAR luciferase reporter in RhoA-null keratinocytes. Inhibition of the RhoA effector ROCK in control cells reproduced this phenotype. ATRA and retinal, but not retinol increased RAR reporter activity of keratinocytes with impaired RhoA/ROCK signaling, suggesting that retinol metabolism is regulated by RhoA/ROCK signaling. Furthermore a significant percentage of known ATRA target genes displayed altered expression in RhoA-null keratinocytes. These data reveal an unexpected link between the cytoskeletal regulator RhoA and retinoid signaling and uncover a novel pathway by which RhoA regulates gene expression.
广泛表达的小GTP酶RhoA对胚胎发育至关重要，且在不同癌症中发生突变。在功能上，它被很好地描述为肌动蛋白细胞骨架的调节剂，但其在基因调控中的作用却知之甚少。利用缺失RhoA基因的原代小鼠角质形成细胞，我们现在一直在探索RhoA的缺失如何影响基因表达。通过进行转录因子报告基因检测，我们发现RhoA基因缺失的角质形成细胞中RAR荧光素酶报告基因的活性显著降低。在对照细胞中抑制RhoA效应器ROCK可重现这一表型。全反式维甲酸（ATRA）和视黄醛，但不是视黄醇，增加了RhoA/ROCK信号受损的角质形成细胞的RAR报告基因活性，表明视黄醇代谢受RhoA/ROCK信号调控。此外，相当比例的已知ATRA靶基因在RhoA基因缺失的角质形成细胞中表达发生改变。这些数据揭示了细胞骨架调节剂RhoA与类视黄醇信号之间意想不到的联系，并揭示了RhoA调节基因表达的新途径。
