title: RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism.
abstract: 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.
authors.affiliation: a Department of Biomedical Sciences , BRIC, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Alberto
authors.initials: A
authors.lastname: García-Mariscal
authors.affiliation: a Department of Biomedical Sciences , BRIC, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Karine
authors.initials: K
authors.lastname: Peyrollier
authors.affiliation: a Department of Biomedical Sciences , BRIC, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Astrid
authors.initials: A
authors.lastname: Basse
authors.affiliation: a Department of Biomedical Sciences , BRIC, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Esben
authors.initials: E
authors.lastname: Pedersen
authors.affiliation: b Laboratory of Nutritional Bioactivation and Bioanalysis, Research Center of Molecular Medicine, University of Debrecen , Hungary.
authors.forename: Ralph
authors.initials: R
authors.lastname: Rühl
authors.affiliation: c Department of Basic Medical Sciences , Faculty of Medicine and Health Sciences, Ghent University , Ghent , Belgium.
authors.forename: Jolanda
authors.identifier: 0000-0003-0645-0435
authors.initials: J
authors.lastname: van Hengel
authors.affiliation: a Department of Biomedical Sciences , BRIC, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
mesh_terms: D000818:Animals; D048429:Cell Size; D005786:Gene Expression Regulation; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D051379:Mice; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D014801:Vitamin A / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D008024:Ligands; D012176:Retinoids; D014801:Vitamin A; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: ROCK; RhoA; retinoic acid; skin; stem cells