title: KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun.
abstract: Loss-of-function mutations in the KRIT1 gene (CCM1) have been associated with the pathogenesis of cerebral cavernous malformations (CCM), a major cerebrovascular disease. However, KRIT1 functions and CCM pathogenetic mechanisms remain incompletely understood. Indeed, recent experiments in animal models have clearly demonstrated that the homozygous loss of KRIT1 is not sufficient to induce CCM lesions, suggesting that additional factors are necessary to cause CCM disease. Previously, we found that KRIT1 is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent ROS-induced cellular dysfunctions, including a reduced ability to maintain a quiescent state. Here, we show that KRIT1 loss of function leads to enhanced expression and phosphorylation of the redox-sensitive transcription factor c-Jun, as well as induction of its downstream target COX-2, in both cellular models and human CCM tissues. Furthermore, we demonstrate that c-Jun upregulation can be reversed by either KRIT1 re-expression or ROS scavenging, whereas KRIT1 overexpression prevents forced upregulation of c-Jun induced by oxidative stimuli. Taken together with the reported role of c-Jun in vascular dysfunctions triggered by oxidative stress, our findings shed new light on the molecular mechanisms underlying KRIT1 function and CCM pathogenesis.
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Goitre
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Luca
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Braggion
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Trapani
authors.affiliation: Department of Neuroscience, University of Torino, Torino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Guglielmotto
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Biasi
authors.affiliation: EuroClone SpA Research Laboratory, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Forni
authors.affiliation: Department of Agriculture, Forest and Food Sciences, Plant Genetics and Breeding, University of Torino, Grugliasco (Torino), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Moglia
authors.affiliation: Department of Biotechnologies, Chemistry, and Pharmacy, University of Siena, Siena, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Trabalzini
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy. Electronic address: francesco.retta@unito.it.
authors.forename: Saverio Francesco
authors.initials: SF
authors.lastname: Retta
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000075927:KRIT1 Protein; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases
keywords: COX-2; Cellular antioxidant defense mechanisms; Cerebral cavernous malformations; Free radicals; KRIT1; Reactive oxygen species; c-Jun