Regulation of FOXO Factors in Mammalian Cells

Brown, Abigail K.; Webb, Ashley E.

doi:10.1016/bs.ctdb.2017.10.006

Cited by 128 publications

(100 citation statements)

References 126 publications

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“…Hence, high levels of H 2 O 2 promote Akt phosphorylation due to PTEN redox-mediated inactivation. Once activated, Akt may directly phosphorylate FoxO family, which participate in cellular transcription programs including metabolism, ROS detoxification, and mitochondrial biogenesis trough PGC-1α [29,99].…”

Section: Tissue-specificmentioning

confidence: 99%

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Rius‐Pérez

Torres-Cuevas

Millán

et al. 2020

Oxidative Medicine and Cellular Longevity

436

292

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Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

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Section: Tissue-specificmentioning

confidence: 99%

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Rius‐Pérez

Torres-Cuevas

Millán

et al. 2020

Oxidative Medicine and Cellular Longevity

436

292

View full text Add to dashboard Cite

show abstract

“…Forkhead Box O (FOXO) transcription factors are also a target of oxidative stress. Oxidative stress indirectly activates FOXO by ROS-mediated activation of JNK kinase, which phosphorylates both FOXO and 14-3-3 protein, promoting the release of FOXO factors, leading to subsequent nuclear translocation and transcriptional activity [171]. In kidneys from a unilateral ureteral obstruction model (UUO) at day 7, FOXO3 activation increased both the mRNA and protein levels of key autophagy proteins including Ulk1, beclin-1, Atg9A, Atg4B, and Bnip3 [172], suggesting that FOXO3 is an important regulator of autophagy in renal tubular epithelial cells.…”

Section: Ros-mediated Regulation Of Autophagy and Its Impact In Kimentioning

confidence: 99%

Molecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease

Kaushal

Chandrashekar

Juncos

2019

IJMS

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Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and oxidative stress play a vital role in the pathogenesis of acute kidney injury and chronic kidney disease, and it is well documented that increased oxidative stress in patients enhances the progression of renal diseases. Oxidative stress activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular oxidized and damaged macromolecules and dysfunctional organelles. In this review, we report the current understanding of the molecular regulation of autophagy in response to oxidative stress in general and in the pathogenesis of kidney diseases. We summarize how the molecular interactions between ROS and autophagy involve ROS-mediated activation of autophagy and autophagy-mediated reduction of oxidative stress. In particular, we describe how ROS impact various signaling pathways of autophagy, including mTORC1-ULK1, AMPK-mTORC1-ULK1, and Keap1-Nrf2-p62, as well as selective autophagy including mitophagy and pexophagy. Precise elucidation of the molecular mechanisms of interactions between ROS and autophagy in the pathogenesis of renal diseases may identify novel targets for development of drugs for preventing renal injury.

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“…FOXO1 is a transcription factor that regulates energy metabolism, specifically increasing cardiac fatty acid uptake and inhibiting glucose utilization 31, 32, 33. Moreover, the activity of FOXO is known to be negatively regulated through phosphorylation by AKT (34). We found the ratio of pFOXO1(Thr24)/FOXO1 was also significantly increased at baseline and after insulin stimulation in SUR2-deleted cardiomyocytes compared with controls (Figure 7F).…”

Section: Resultsmentioning

confidence: 86%