Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Fernandes, Alexandre F.; Guo, Weimin; Zhang, Xinyu; Gallagher, Maurice P.; Ivan, Mircea; Taylor, Allen; Pereira, Paulo; Shang, Fu

doi:10.1016/j.exer.2006.07.024

Cited by 30 publications

(41 citation statements)

References 66 publications

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“…The in vivo effects were not seen when MG132 was injected at day 4 after laser, suggesting that timing of target inhibition is critical (results not shown). Restoration of VEGF-A levels in ␣B-crystallin Ϫ/Ϫ retinas and cells were only partial, which is consistent with the report by Fernandes et al, 36 who found that increases in RPE VEGF-A levels after proteasomal inhibition may be mediated by competing effects on HIF-1␣. The effects of proteasomal inhibition on angiogenesis in vivo are even more complex; inhibitors of the proteasome also can inhibit angiogenesis through regulation of multiple targets of the proteasome, including apoptosis mediators 37 and components of the inflammatory response, 38 and in models of tumor angiogenesis, MG132 has been reported to inhibit VEGF-A production.…”

Section: Discussionsupporting

confidence: 81%

αB-crystallin regulation of angiogenesis by modulation of VEGF

Kase

Sonoda

et al. 2010

Blood

145

164

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Section: Discussionsupporting

confidence: 81%

αB-crystallin regulation of angiogenesis by modulation of VEGF

Kase

Sonoda

et al. 2010

Blood

145

164

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“…Oxidative inactivation of the proteasome and the subsequent alterations in several signaling pathways, such as NF-B and p38 MAPK, are plausible mechanisms that underlie the oxidative stress-induced upregulation of IL-8, one of the most potent proinflammatory and proangiogenic chemokines. Given the function of the UPP in regulating IL-8, vascular endothelial growth factor and MCP-1 in RPE cells (27) and the roles of these chemokines and growth factor in the pathogenesis of AMD (38, 39, 86), impairment of the UPP in RPE could significantly contribute to the development of AMD. Thus, protecting the UPP from oxidative inactivation may become a valid therapeutic strategy for prevention of AMD and other age-and inflammation-related diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Real Time RT-PCR-Total RNA extraction from ARPE-19 cells and real time RT-PCR analysis were performed as described (27). For IL-8, the forward primer was: 5Ј-AAAC-CACCGGAAGGAACCAT-3Ј and the reverse primer was: 5Ј-CCTTCACACAGAGCTGCAGAAA-3Ј.…”

Section: Methodsmentioning

confidence: 99%

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Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Fernandes

Zhou

Zhang

et al. 2008

Journal of Biological Chemistry

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Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. Stress-induced overproduction of inflammatory cytokines, such as interleukin-8 (IL-8), is one of the early events of inflammation. The objective of this study was to elucidate mechanistic links between oxidative stress and overproduction of IL-8 in retinal pigment epithelial (RPE) cells. We found that exposure of RPE cells to H 2 O 2 , paraquat, or A2E-mediated photooxidation resulted in increased expression and secretion of IL-8. All of these oxidative stressors also inactivated the proteasome in RPE cells. In contrast, tert-butylhydroperoxide (TBH), a lipophilic oxidant that did not stimulate IL-8 production, also did not inactivate the proteasome. Moreover, prolonged treatment of RPE cells with proteasome-specific inhibitors recapitulated the stimulation of IL-8 production. These data suggest that oxidative inactivation of the proteasome is a potential mechanistic link between oxidative stress and up-regulation of the proinflammatory IL-8. The downstream signaling pathways that govern the production of IL-8 include NF-B and p38 MAPK. Proteasome inhibition both attenuated the activation and delayed the turnoff of NF-B, resulting in biphasic effects on the production of IL-8. Prolonged proteasome inhibition (>2 h) resulted in activation of p38 MAPK via activation of MKK3/6 and increased the production of IL-8. Chemically inhibiting the p38 MAPK blocked the proteasome inhibition-induced up-regulation of IL-8. Together, these data indicate that oxidative inactivation of the proteasome and the related activation of the p38 MAPK pathway provide a potential link between oxidative stress and overproduction of proinflammatory cytokines, such as IL-8.Oxidative stress, which refers to cellular damage caused by reactive oxygen species, has been implicated in the onset and progression of many age-related diseases, including age-related macular degeneration (AMD), 3 arthritis, atherosclerosis, and certain types of cancer (1-3). Inflammatory events are also known to participate in the pathogenesis of these age-related diseases. The activation of redox-sensitive transcription factors may be involved in triggering the expression of proinflammatory cytokines (2). However, the molecular links between oxidative stress and inflammation are not fully understood.Retina has the highest metabolic rate and oxygen consumption in the body. The high metabolic rate and oxygen consumption is usually accompanied by generation of reactive oxygen species. Chronic exposure to light could also increase the production of reactive oxygen species (1, 4). Therefore, retinal pigment epithelium (RPE) is a primary target of oxidative stress.Age-related accumulation of lipofuscin in RPE is another source of oxidative stress. Lipofuscin is a mixture of nondegradable protein-lipid aggregates derived from the ingestion of photoreceptor outer segments (5). A2E is the major fluorophore of lipofuscin and acts as a photosensitizer to generate reactive oxygen spe...

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“…29,30 However, recent studies have revealed the importance of the HIF-independent, PGC-1/ERR- Figure 1. Definition of intense physiological light for mice.…”

Section: Vegf Upregulation In Rpe Cells Treated With Os Is Mediated Bmentioning

confidence: 99%

Intense Physiological Light Upregulates Vascular Endothelial Growth Factor and Enhances Choroidal Neovascularization via Peroxisome Proliferator-Activated Receptor γ Coactivator-1α in Mice

Ueta

Inoue

Yuda

et al. 2012

ATVB

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Objectives— Toxicity of intense light to facilitate the development of neovascular age-related macular degeneration has been a health concern although the mechanism remains unclear. Methods and Results— Effects of intense, but within physiological range, light on retinal pigment epithelium, a major pathogenic origin of age-related macular degeneration were studied in mice. Intense physiological light upregulated vascular endothelial growth factor (VEGF) expression in retinal pigment epithelium, independent of circadian rhythm, which resulted in enhancement of choroidal neovascularization. In rd1/rd1 mice or Crx −/− mice that do not possess outer segment structure, light exposure did not induce VEGF, indicating that VEGF upregulation by light depended on increased outer segment phagocytosis by retinal pigment epithelium. In retinal pigment epithelium cells phagocytosing increased amount of outer segment, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) not hypoxia-inducible factor-1α was induced, leading to VEGF upregulation. The VEGF upregulation and choroidal neovascularization enhancement were abrogated in PGC-1α −/− mice and estrogen-related receptor-α −/− mice, indicating the involvement of PGC-1α/estrogen-related receptor-α pathway. Conclusions— Intense physiological light is involved in choroidal neovascularization through excess outer segment phagocy-tosis and VEGF upregulation mediated by PGC-1α in vivo.

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Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Cited by 30 publications

References 66 publications

αB-crystallin regulation of angiogenesis by modulation of VEGF

αB-crystallin regulation of angiogenesis by modulation of VEGF

Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Intense Physiological Light Upregulates Vascular Endothelial Growth Factor and Enhances Choroidal Neovascularization via Peroxisome Proliferator-Activated Receptor γ Coactivator-1α in Mice

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