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KRIT1 Regulates the Homeostasis of Intracellular Reactive Oxygen Species Scarica

Descrizione:
KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by
abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral
hemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be
severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis
mechanisms are still research challenges. We found that KRIT1 plays an important role in molecular mechanisms involved in
the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage. In
particular, we demonstrate that KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS
levels. Conversely, ROS levels in KRIT12/2 cells are significantly and dose-dependently reduced after restoration of KRIT1
expression. Moreover, we show that the modulation of intracellular ROS levels by KRIT1 loss/restoration is strictly correlated
with the modulation of the expression of the antioxidant protein SOD2 as well as of the transcriptional factor FoxO1, a
master regulator of cell responses to oxidative stress and a modulator of SOD2 levels. Furthermore, we show that the KRIT1-
dependent maintenance of low ROS levels facilitates the downregulation of cyclin D1 expression required for cell transition
from proliferative growth to quiescence. Finally, we demonstrate that the enhanced ROS levels in KRIT12/2 cells are
associated with an increased cell susceptibility to oxidative DNA damage and a marked induction of the DNA damage
sensor and repair gene Gadd45a, as well as with a decline of mitochondrial energy metabolism. Taken together, our results
point to a new model where KRIT1 limits the accumulation of intracellular oxidants and prevents oxidative stress-mediated
cellular dysfunction and DNA damage by enhancing the cell capacity to scavenge intracellular ROS through an antioxidant
pathway involving FoxO1 and
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Administrator (admin)
Inviato il
30 Sep 2012
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Autore del file:
Luca Goitre1, Fiorella Balzac1, Simona Degani1, Paolo Degan2, Saverio Marchi3, Paolo Pinton3, Saveri
Inviato il
27 Jun 2011
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