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Title: KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun
Authors: Goitre, Luca
De Luca, Elisa
Braggion, Stefano
Trapani, Eliana
Guglielmotto, Michela
Biasi, Fiorella
Forni, Marco
Moglia, Andrea
Trabalzini, Lorenza 
Retta, Saverio Francesco
Keywords: COX-2; Cellular antioxidant defense mechanisms; Cerebral cavernous malformations; Free radicals; KRIT1; Reactive oxygen species; c-Jun; Animals; Gene Expression Regulation; Hemangioma, Cavernous, Central Nervous System; Humans; JNK Mitogen-Activated Protein Kinases; Microtubule-Associated Proteins; Mutation; Oxidative Stress; Proto-Oncogene Proteins; Reactive Oxygen Species
Issue Date: 2014
Project: None 
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.
ISSN: 0891-5849
DOI: 10.1016/j.freeradbiomed.2013.11.020
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