KRIT1 Regulates the Homeostasis of Intracellular Reactive Oxygen Species

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 KRIT1−/− 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 KRIT1−/− cells are associated with an increased cell susceptibility to oxidative DNA damage and a marked induction of the DNA damage sensor and repair gene Gadd45α, 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 SOD2, thus providing novel and useful insights into the understanding of KRIT1 molecular and cellular functions

Low dose Rituximab for pre-emptive treatment of Epstein Barr virus reactivation after allogenic hematopoietic stem cell transplantation

International audienc

Observatoire de la leucémie myéloïde chronique : un outil unique pour une étude multicentrique dans la « vraie vie » en France

# 09-10International audienc

The Spliceosome: An Another Regulating System of Gene Expression Deregulated in CP-CML CD34+CD15- Cells

International audienc

Le spliceosome : un autre mécanisme de régulation des gènes impliqués dans l’hétérogénéité intra-clonale de la Leucémie Myéloïde Chronique ?

# 09-01International audienc

Determinants of audit report lag: some evidence from the Athens stock exchange

The timely publication of corporate financial information depends on the time taken to complete the audit. The audit report lag is a particularly critical factor in emerging and newly developed capital markets where the audited financial statements in the annual report are the only reliable source of information available to investors. This paper examines the audit report lag of companies listed on the Athens Stock Exchange at the time of its transition from an emerging market to a newly developed capital market. A statistically significant association is found between audit report lag and type of auditor, audit fees, number of remarks in the audit report, the presence of extraordinary items, and an expression of uncertainty in the audit report. The results suggest that audit report lag is reduced by appointing an international audit firm or paying a premium audit fee, but is extended by aspects of potentially bad news