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Updated: May 5, 2026
Inducible and Reversible Dominant-negative DN Protein Inhibition
Published on: January 7, 2019
KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun
Luca Goitre1, Elisa De Luca1, Stefano Braggion1
1Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (Torino), Italy.
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.
Insights
Loss of KRIT1 function elevates c-Jun and COX-2, contributing to cerebral cavernous malformations (CCM). Restoring KRIT1 or reducing reactive oxygen species (ROS) reverses these effects, clarifying CCM pathogenesis.
Area of Science:
- Molecular Biology
- Genetics
- Vascular Biology
Background:
- Loss-of-function mutations in the KRIT1 gene (CCM1) are linked to cerebral cavernous malformations (CCM).
- KRIT1's precise role in CCM pathogenesis and its cellular functions are not fully understood.
- Previous research indicates KRIT1 is crucial for maintaining intracellular reactive oxygen species (ROS) homeostasis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which KRIT1 loss contributes to CCM pathogenesis.
- To investigate the relationship between KRIT1, ROS, and the transcription factor c-Jun in CCM development.
Main Methods:
- Utilized cellular models and human CCM tissues to study KRIT1 function.
- Examined the expression and phosphorylation of c-Jun and the induction of its target COX-2.
- Assessed the impact of KRIT1 re-expression, ROS scavenging, and KRIT1 overexpression on c-Jun levels.
Main Results:
- KRIT1 loss of function resulted in increased expression and phosphorylation of c-Jun and elevated COX-2 levels.
- c-Jun upregulation was reversible by KRIT1 re-expression or ROS scavenging.
- KRIT1 overexpression inhibited oxidative stress-induced c-Jun upregulation.
Conclusions:
- KRIT1 loss promotes CCM pathogenesis through enhanced c-Jun activity, linked to ROS.
- Findings highlight the critical role of KRIT1 in regulating redox-sensitive pathways like c-Jun/COX-2.
- This study provides new insights into the molecular basis of KRIT1 function and CCM disease mechanisms.
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