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Regulation of reactive oxygen species homeostasis by peroxiredoxins and c-Myc.

ABSTRACT: Peroxiredoxins (Prxs) are highly conserved proteins found in most organisms, where they function primarily to scavenge reactive oxygen species (ROS). Loss of the most ubiquitous member of the family, Prx1, is associated with the accumulation of oxidatively damaged DNA and a tumor-prone phenotype. Prx1 interacts with the transcriptional regulatory domain of the c-Myc oncoprotein and suppresses its transforming activity. The DNA damage in tissues of prx1-/- mice is associated in some cases with only modest increases in total ROS levels. However, these cells show dramatic increases in nuclear ROS and reduced levels of cytoplasmic ROS, which explains their mutational susceptibility. In the current work, we have investigated whether changes in other ROS scavengers might account for the observed ROS redistribution pattern in prx1-/- cells. We show approximately 5-fold increases in Prx5 levels in prx1-/- embryo fibroblasts relative to prx1+/+ cells. Moreover, Prx5 levels normalize when Prx1 expression is restored. Prx5 levels also appear to be highly dependent on c-Myc, and chromatin immunoprecipitation experiments showed differential occupancy of c-Myc and Prx1 complexes at E-box elements in the prx5 gene proximal promoter. This study represents a heretofore unreported mechanism for the c-Myc-dependent regulation of one Prx family member by another and identifies a novel means by which cells reestablish ROS homeostasis when one of these family members is compromised.

SUBMITTER: Graves JA

PROVIDER: S-EPMC2649099 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 Gadd45alpha, 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.

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Regulation of reactive oxygen species homeostasis by peroxiredoxins and c-Myc.

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