Neuroprotectin D1 Induces Dephosphorylation of Bcl-xL in a PP2A-dependent Manner during Oxidative Stress and Promotes Retinal Pigment Epithelial Cell Survival

Antony, Rajee; Lukiw, Walter J.; Bazán, Nicolás G.

doi:10.1074/jbc.m109.095232

Cited by 67 publications

(44 citation statements)

References 54 publications

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“…PP2A, which is a ubiquitously expressed serine/threonine phosphatase, plays an important role in the regulation of cellular functions, including cell-cycle control and survival (28). Previous studies showed that PP2A dephosphorylated Bcl-2 family members, including Bcl-2 and Bcl-xL, and controlled its antiapoptotic activity (58,59). In this study, we showed that PP6, which belongs to the PP2A subfamily, played an important role in the regulation of Bcl-xL.…”

Section: Discussionmentioning

confidence: 63%

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Kajihara

Sakamoto

Tanabe

et al. 2014

The Journal of Immunology

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Crosslinking BCR in the immature B cell line WEHI-231 causes apoptosis. We found that Bcl-xL was degraded by polyubiquitination upon BCR crosslinking and in this study explored the mechanism that controls the degradation of Bcl-xL. Ser62 of Bcl-xL was phosphorylated by JNK to trigger polyubiquitination, and this was opposed by serine/threonine protein phosphatase 6 (PP6) that physically associated with Bcl-xL. We show BCR crosslinking decreased PP6 activity to allow Ser62 phosphorylation of Bcl-xL. CD40 crosslinking rescues BCR-induced apoptosis, and we found PP6 associated with CD40 and PP6 activation in response to CD40. Our data suggest that PP6 activity is regulated to control apoptosis by modulating Ser62 phosphorylation of Bcl-xL, which results in its polyubiquitination and degradation.

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Section: Discussionmentioning

confidence: 63%

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Kajihara

Sakamoto

Tanabe

et al. 2014

The Journal of Immunology

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“…These conditions are known to trigger apoptosis in other cell types, but normally the RPE appears to be resilient in part due to specific modifications of the apoptotic pathway. Our group 15 and others have shown that normal RPE has unusually low levels of caspase-8, 16 high levels of antiapoptotic Bcl-2 family proteins, 15,17 and neuroprotectin-D1, 18 all of which serve to inactivate proapoptotic and proinflammatory signaling pathways. We now seek to determine if these antiapoptotic conditions degrade during aging so that RPE cells become vulnerable to normal proapoptotic stressors, creating a tipping point beyond which retinal homeostasis is lost along with visual function.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Susceptibility to Apoptosis in Human Retinal Pigment Epithelial Cells Is Triggered by Disruption of p53–Mdm2 Association

Bhattacharya¹,

Chaum

Johnson

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Relatively little is known about the contribution of p53/Mdm2 pathway in apoptosis of retinal pigment epithelial (RPE) cells or its possible link to dysfunction of aging RPE or to related blinding disorders such as age-related macular degeneration (AMD).METHODS. Age-associated changes in p53 activation were evaluated in primary RPE cultures from human donor eyes of various ages. Apoptosis was evaluated by activation of caspases and DNA fragmentation. Gene-specific small interfering RNA was used to knock down expression of p53. RESULTS.We observed that the basal rate of p53-dependent apoptosis increased in an age-dependent manner in human RPE. The age-dependent increase in apoptosis was linked to alterations in several aspects of the p53 pathway. p53 phosphorylation Ser15 was increased through the stimulation of ATM-Ser1981. p53 acetylation Lys379 was increased through the inhibition of SIRT1/2. These two posttranslational modifications of p53 blocked the sequestration of p53 by Mdm2, thus resulting in an increase in free p53 and of p53 stimulation of apoptosis through increased expression of PUMA (p53 upregulated modulator of apoptosis) and activation of caspase-3. Aged RPE also had reduced expression of antiapoptotic Bcl-2, which contributed to the increase in apoptosis. Of particular interest in these studies was that pharmacologic treatments to block p53 phosphorylation, acetylation, or expression were able to protect RPE cells from apoptosis.CONCLUSIONS. Our studies suggest that aging in the RPE leads to alterations of specific checkpoints in the apoptotic pathway, which may represent important molecular targets for the treatment of RPE-related aging disorders such as AMD. (Invest Ophthalmol Vis Sci. 2012;53:8350-8366) DOI:10.1167/ iovs.12-10495 A major challenge in vision research is the identification of the causative factors that lead to declines in retinal function that will ultimately result in age-related macular degeneration (AMD) for a projected 3 million individuals in the United States with neovascular AMD and/or geographic atrophy by 2020. 1 One promising strategy in understanding this multifactorial disease process is to identify and track agedependent changes in cellular pathways, especially in cells of the retinal pigment epithelium (RPE) because these represent the gatekeepers whose loss of functional integrity has been linked to retinal aging.2-4 RPE cells constitute a major component of the blood-retinal barrier (BRB) and loss of integrity of tight junctions (TJs) and adherens junctions (AJs) in RPE can disrupt photoreceptor homeostasis. 5-9 RPE cells also phagocytosize tips of outer segments normally shed by photoreceptors, generate melanosomes to function as a light and heat sink, provide trophic factors, and recycle visual pigments. Many of the hallmarks of AMD reflect malfunctions of these RPE-related pathways, including photobleaching of melanosomes, accumulation of lipofuscin granules, impairment of outer segment phagocytosis, formation of drusen, and breakdown of the BRB in a...

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“…Similar to a previous study (25), PP activity was gradually decreased after HPO treatment and was significantly lower than that with vehicle treatment at 2 h (Table 1) Cells were pretreated with black soybean seed coat extract (BE, 50 mg/mL) for 2 h (22-0 h time points) and then treated with hydrogen peroxide (HPO, 500 mm) for 2 h (0-2 h time points). Data were normalized to protein concentrations, are expressed relative to the 22 h control and are presented as means6SEM of 6 replicates.…”

Section: Resultsmentioning

confidence: 66%

Black Soybean Seed Coat Extract Prevents Hydrogen Peroxide-Mediated Cell Death via Extracellular Signal-Related Kinase Signalling in HepG2 Cells

Hashimoto

Oki

Sasaki

et al. 2015

J Nutr Sci Vitaminol

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Summary Oxidative stress reduces cell viability and contributes to disease processes. Flavonoids including anthocyanins and proanthocyanidins reportedly induce intracellular antioxidant defence systems. Thus, in this study, we examined the antioxidant effects of a commercial extract from black soybean seed coats (BE), which are rich in anthocyanin and proanthocyanidin, and investigated the associated intracellular mechanisms in HepG2 cells. HepG2 cells treated with hydrogen peroxide (HPO) showed 60% viability, whereas pretreatment with BE-containing media for 2 h ameliorated HPO-mediated cell death by up to 90%. Pretreatment with BE for 2 h partially blocked HPO-mediated activation of ERK in HepG2 cells, and that for 1 h led to a 20% increase in intracellular total protein phosphatase (PP) activity, which is known to deactivate protein kinases. These results indicate that BE prevents HPO-mediated cell damage by inhibiting ERK signalling, potentially via PPs.

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Neuroprotectin D1 Induces Dephosphorylation of Bcl-xL in a PP2A-dependent Manner during Oxidative Stress and Promotes Retinal Pigment Epithelial Cell Survival

Cited by 67 publications

References 54 publications

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Age-Related Susceptibility to Apoptosis in Human Retinal Pigment Epithelial Cells Is Triggered by Disruption of p53–Mdm2 Association

Black Soybean Seed Coat Extract Prevents Hydrogen Peroxide-Mediated Cell Death via Extracellular Signal-Related Kinase Signalling in HepG2 Cells

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