Dataset Information

A critical role of Fas-associated protein with death domain phosphorylation in intracellular reactive oxygen species homeostasis and aging.

ABSTRACT:

Aim

Reactive oxygen species (ROS) plays important roles in aging. However, the specific mechanisms for intracellular ROS accumulation, especially during aging, remain elusive.

Results

We have reported that Fas-associated protein with death domain (FADD) phosphorylation abolishes the recruitment of phosphatase type 2A C subunit (PP2Ac) to protein kinase C (PKC)?II, which specifically regulates mitochondrial ROS generation by p66shc. Here, we have studied the role of FADD phosphorylation in an FADD constitutive-phosphorylation mutation (FADD-D) mouse model. In FADD-D mice, the constitutive FADD phosphorylation led to ROS accumulation (hydrogen peroxide [H?O?]), in a process that was dependent on PKC? and accompanied by increased PKC? and p66shc phosphorylation, impaired mitochondrial integrity, and enhanced sensitivity to oxidative stress-mediated apoptosis. Moreover, FADD-D mice exhibited premature aging-like phenotypes, including DNA damage, cellular senescence, and shortened lifespan. In addition, we demonstrate that FADD phosphorylation and the recruitment of PP2A and FADD to PKC? are induced responses to oxidative stress, and that the extent of FADD phosphorylation in wild-type mice was augmented during aging, accompanied by impairment of the interaction between PKC? and PP2A.

Innovation

The present study first addresses the role of FADD phosphorylation in aging through controlling mitochondrial ROS specifically generated by PKC?.

Conclusion

These data identify that FADD phosphorylation is critical for the PKC?-p66shc signaling route to generate H?O? and to implicate enhanced FADD phosphorylation as a primary cause of ROS accumulation during aging.

SUBMITTER: Cheng W

PROVIDER: S-EPMC4048578 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Publications

A critical role of Fas-associated protein with death domain phosphorylation in intracellular reactive oxygen species homeostasis and aging.

Cheng Wei W Zhang Rong R Yao Chun C He Liangqiang L Jia Kunzhi K Yang Bingya B Du Pan P Zhuang Hongqin H Chen Jianxiang J Liu Zexu Z Ding Xinxin X Hua Zichun Z

Antioxidants & redox signaling 20140306 1

<h4>Aim</h4>Reactive oxygen species (ROS) plays important roles in aging. However, the specific mechanisms for intracellular ROS accumulation, especially during aging, remain elusive.<h4>Results</h4>We have reported that Fas-associated protein with death domain (FADD) phosphorylation abolishes the recruitment of phosphatase type 2A C subunit (PP2Ac) to protein kinase C (PKC)βII, which specifically regulates mitochondrial ROS generation by p66shc. Here, we have studied the role of FADD phosphoryl ...[more]

PMID: 24295239

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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.

Dataset Information

A critical role of Fas-associated protein with death domain phosphorylation in intracellular reactive oxygen species homeostasis and aging.

Aim

Results

Innovation

Conclusion

Publications

A critical role of Fas-associated protein with death domain phosphorylation in intracellular reactive oxygen species homeostasis and aging.

Similar Datasets

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