| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Goitre, Luca De Luca, Elisa Braggion, Stefano Trapani, Eliana Guglielmotto, Michela Biasi, Fiorella Forni, Marco Moglia, Andrea Trabalzini, Lorenza Retta, Saverio Francesco |
| Description |
Country affiliation: Italy Author Affiliation: Goitre L ( Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.); De Luca E ( Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.); Braggion S ( Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.); Trapani E ( Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.); Guglielmotto M ( Department of Neuroscience, University of Torino, Torino, Italy.); Biasi F ( Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.); Forni M ( EuroClone SpA Research Laboratory, Torino, Italy.); Moglia A ( Department of Agriculture, Forest and Food Sciences, Plant Genetics and Breeding, University of Torino, Grugliasco (Torino), Italy.); Trabalzini L ( Department of Biotechnologies, Chemistry, and Pharmacy, University of Siena, Siena, Italy.); Retta SF ( Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy. Electronic address: francesco.retta@unito.it.) |
| 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. |
| File Format |
HTM / HTML |
| ISSN |
08915849 |
| e-ISSN |
18734596 |
| DOI |
10.1016/j.freeradbiomed.2013.11.020 |
| Journal |
Free Radical Biology and Medicine |
| Volume Number |
68 |
| Language |
English |
| Publisher |
Elsevier |
| Publisher Date |
2014-03-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Free radicals biology Hemangioma, Cavernous, Central Nervous System Genetics Jnk Mitogen-activated Protein Kinases Metabolism Microtubule-associated Proteins Oxidative Stress Proto-oncogene Proteins Animals Gene Expression Regulation Pathology Mutation Reactive Oxygen Species Research Support, Non-u.s. Gov't |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Physiology (medical) Biochemistry |
