PKCζ-dependent upregulation of p27kip1 contributes to oxidative stress induced retinal pigment epithelial cell multinucleation

Rajapakse, Dinusha; Chen, Mei; Curtis, Tim M.; Xu, Heping

doi:10.18632/aging.101299

Cited by 12 publications

(12 citation statements)

References 40 publications

(49 reference statements)

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“…This cell death stimulation could be additionally enforced by the downexpression of CDKN2D and the overexpression of CDKN1B. [93,[126][127][128][129][130][131][132][133][134] ZINC FINGERS TRANSCRIPTION FACTORS…”

Section: Retinoic Acid Cycle (Rdh5 Mkv)mentioning

confidence: 99%

RETRACTED ARTICLE: Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis

et al. 2018

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Retinitis pigmentosa (RP) is a very heterogeneous inherited ocular disorder group characterized by progressive retinal disruption. Retinal pigment epithelium (RPE) degeneration, due to oxidative stress which arrests the metabolic support to photoreceptors, represents one of the principal causes of RP. Here, the role of oxidative stress in RP onset and progression was analyzed by a comparative whole transcriptome analysis of human RPE cells, treated with 100 µg/ml of oxLDL and untreated, at different time points. Experiment was thrice repeated and performed on Ion Proton TM sequencing system. Data analysis, including low quality reads trimming and gene expression quantification, was realized by CLC Genomics Workbench software. The whole analysis highlighted 14 clustered "macro-pathways" and many sub-pathways, classified by selection of 5271 genes showing the highest alteration of expression. Among them, 23 genes were already known to be RP causative ones (15 over-expressed and 8 down-expressed), and their enrichment and intersection analyses highlighted new 77 candidate related genes (49 over-expressed and 28 down-expressed). A final filtering analysis then highlighted 29 proposed candidate genes. This data suggests that many new genes, not yet associated with RP, could influence its etiopathogenesis.

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Section: Retinoic Acid Cycle (Rdh5 Mkv)mentioning

confidence: 99%

RETRACTED ARTICLE: Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis

et al. 2018

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“…Incubation with OxPOS also led to activation of protein kinase C (PKC) isoforms and PKC-dependent upregulation of the Cdk inhibitor p27kip. Suppression of cell proliferation was observed with multinucleate RPE [64], of which the latter is associated with pathology in the retina. Moreover, OxPOS induced expression of the senescence marker β-galactosidase.…”

Section: Discussionmentioning

confidence: 96%

An In-Vitro Cell Model of Intracellular Protein Aggregation Provides Insights into RPE Stress Associated with Retinopathy

Keeling

Culling

Johnston

et al. 2020

IJMS

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Impaired cargo trafficking and the aggregation of intracellular macromolecules are key features of neurodegeneration, and a hallmark of aged as well as diseased retinal pigment epithelial (RPE) cells in the eye. Here, photoreceptor outer segments (POS), which are internalized daily by RPE cells, were modified by UV-irradiation to create oxidatively modified POS (OxPOS). Oxidative modification was quantified by a protein carbonyl content assay. Human ARPE-19 cells were synchronously pulsed with POS or OxPOS to study whether oxidatively modified cargos can recapitulate features of RPE pathology associated with blinding diseases. Confocal immunofluorescence microscopy analysis showed that OxPOS was trafficked to LAMP1, LAMP2 lysosomes and to LC3b autophagy vacuoles. Whilst POS were eventually degraded, OxPOS cargos were sequestered in late compartments. Co-localization of OxPOS was also associated with swollen autolysosomes. Ultrastructural analysis revealed the presence of electron-dense OxPOS aggregates in RPE cells, which appeared to be largely resistant to degradation. Measurement of cellular autofluorescence, using parameters used to assess fundus autofluorescence (FAF) in age-related macular disease (AMD) patients, revealed that OxPOS contributed significantly to a key feature of aged and diseased RPE. This in vitro cell model therefore represents a versatile tool to study disease pathways linked with RPE damage and sight-loss.

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“…Cancers, such as gliomas [ 73 , 74 , 75 ] and colon cancer [ 76 ], present an upregulation of the canonical WNT/β-catenin pathway associated with a decrease of PPARγ expression [ 77 ]. The process of fibrosis exhibits the same mechanism [ 78 , 79 , 80 ]. Neurodegenerative diseases are classified in two categories [ 34 ], i.e., diseases that present a downregulation of the canonical WNT/β-catenin pathway and an upregulation of PPARγ, such as Alzheimer’s disease [ 81 , 82 , 83 ], and diseases with an upregulation of the canonical WNT/β-catenin pathway whereas PPARγ is decreased, such as exudative age related macular degeneration [ 84 , 85 ], amyotrophic lateral sclerosis [ 86 ], and multiple sclerosis [ 18 ].…”

Section: Crosstalk Between Pparγ and Canonical Wnt/β-catenin Pathwmentioning

confidence: 99%

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

Vallée

Lecarpentier²,

Guillevin

et al. 2018

IJMS

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Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

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PKCζ-dependent upregulation of p27kip1 contributes to oxidative stress induced retinal pigment epithelial cell multinucleation

Cited by 12 publications

References 40 publications

RETRACTED ARTICLE: Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis

RETRACTED ARTICLE: Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis

An In-Vitro Cell Model of Intracellular Protein Aggregation Provides Insights into RPE Stress Associated with Retinopathy

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

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