Signal transducer and activator of transcription 3 (STAT3) signaling in retinal pigment epithelium cells

Patel, Amit K.; Syeda, Sarah; Hackam, Abigail S.

doi:10.4161/jkst.25434

Cited by 14 publications

(13 citation statements)

References 43 publications

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“…STAT3 has been demonstrated to enhance choroidal neovascularization, and this factor is known to be activated by elevated IL-10 levels [ 62 ]. STAT3 has been postulated to be a potential biomarker for diagnosis and treatment of AMD due to its regulatory role in the survival of RPE cells; it is also recognized as playing a role in the regulation of visual cycle and the inflammatory response [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Tear film proteome in age-related macular degeneration

Winiarczyk

Adaszek

et al. 2018

Graefes Arch Clin Exp Ophthalmol

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PurposeAge-related macular degeneration (AMD) is the main reason for blindness in elderly people in the developed countries. Current screening protocols have limitations in detecting the early signs of retinal degeneration. Therefore, it would be desirable to find novel biomarkers for early detection of AMD. Development of novel biomarkers would help in the prevention, diagnostics, and treatment of AMD. Proteomic analysis of tear film has shown promise in this research area. If an optimal set of biomarkers could be obtained from accessible body fluids, it would represent a reliable way to monitor disease progression and response to novel therapies.MethodsTear films were collected on Schirmer strips from a total of 22 patients (8 with wet AMD, 6 with dry AMD, and 8 control individuals). 2D electrophoresis was used to separate tear film proteins prior to their identification with matrix-assisted laser desorption/ionization time of flight spectrometer (MALDI-TOF/TOF) and matching with functional databases.ResultsA total of 342 proteins were identified. Most of them were previously described in various proteomic studies concerning AMD. Shootin-1, histatin-3, fidgetin-like protein 1, SRC kinase signaling inhibitor, Graves disease carrier protein, actin cytoplasmic 1, prolactin-inducible protein 1, and protein S100-A7A were upregulated in the tear film samples isolated from AMD patients and were not previously linked with this disease in any proteomic analysis.ConclusionThe upregulated proteins supplement our current knowledge of AMD pathogenesis, providing evidence that certain specific proteins are expressed into the tear film in AMD. As far we are aware, this is the first study to have undertaken a comprehensive in-depth analysis of the human tear film proteome in AMD patients.Electronic supplementary materialThe online version of this article (10.1007/s00417-018-3984-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Tear film proteome in age-related macular degeneration

Winiarczyk

Adaszek

et al. 2018

Graefes Arch Clin Exp Ophthalmol

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“…3H). We also examined the transcriptional levels of genes critical to RPE functions, such as those implicated in mediating cell junction to nuclear signaling (␤-catenin) (72), extracellular matrix remodeling and/or adhesion (collagen VI ␣1/3, versican) (73,74), inflammation and cytokine signaling (Stat3, Stat5, and CXCR4 (CXC chemokine receptor type 4 (fusin/ CD184)) (64,75,76), receptor tyrosine kinase signaling (ErbB1/2) (22, 77), and markers of RPE (cytokeratin 18, miR-224, and miR200b) (78). We found that RPE of RPE-cre::Ranbp2 Ϫ/Ϫ mice exhibit strong deregulation of the transcriptional expression of all these genes at P14 (Fig.…”

Section: Cd11bmentioning

confidence: 99%

Selective Impairment of a Subset of Ran-GTP-binding Domains of Ran-binding Protein 2 (Ranbp2) Suffices to Recapitulate the Degeneration of the Retinal Pigment Epithelium (RPE) Triggered by Ranbp2 Ablation

Patil

Saha

Senda

et al. 2014

Journal of Biological Chemistry

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Background: Ranbp2 and its Ran-GTP-binding domains' roles in RPE survival/function, a multidisease target, are elusive. Results: RPE undergoes degeneration, disruptions of proteostasis of Ranbp2 partners, and blood-retinal barrier upon Ranbp2 ablation. Impairment of selective Ran-GTP-binding domains of Ranbp2 suffices to promote RPE degeneration. Conclusion: Ran GTPase regulation by Ranbp2 is vital to RPE. Significance: Ranbp2-dependent targets/mechanisms with therapeutic potential in RPE degeneration are uncovered. The retinal pigment epithelium (RPE) 6 is a critical component of the blood-retinal barrier and maintains retinal homeostasis by filtering damaging light, nourishing the neural retina, replenishing the 11-cis-retinal chromophore to photoreceptors, and phagocytizing damaged (photo-oxidized) outer segments of photoreceptors (1-3). RPE dysfunction underlies disparate diseases promoting RPE degeneration, such as atrophic and neovascular age-related macular degeneration (4 -6), * This work was supported, in whole or in part, by National Institutes of Health Grants EY019492, GM083165, and GM083165-04S1 (to P. A. F.), 2P30-EY005722 (to the Duke University Eye Center), and 5P30NS061789 (to the Duke Neurotransgenic Laboratory). This work was also supported by the Foundation Fighting Blindness bestrophinopathies (7), and various forms of retinal dystrophies (e.g. retinitis pigmentosa, Leber congenital amaurosis) (8 -12). The cause-effect mechanisms of RPE degeneration are not understood, but they appear to arise from the interplay of multifactorial events impinging on heterogeneous genetic predispositions, noxious insults, and senescence that culminate with cytotoxicity to the RPE (13-21). Retinal pigment epithelium (RPE) degeneration underpins diseases triggered by disparate genetic lesions, noxious insultsEmerging studies indicate that the modular and pleiotropic Ranbp2 (Ran (Ras-related nuclear protein)-binding protein 2) plays critical and cell type-dependent roles in cell survival, proliferation, or functions upon intrinsic or extrinsic pathological stressors. For example, haploinsufficiency of Ranbp2 in an inbred genetic background confers neuroprotection to photoreceptor degeneration upon photo-oxidative stress and modulates glucose tolerance (22-24), whereas it increases the susceptibility of mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-elicited Parkinsonism (25) or carcinogenesis (26). Interestingly, RANBP2 is also a substrate for degradation by PARKIN (27,28), whose impairment causes familial and sporadic Parkinson (29 -31) or multisite oncogenesis (32,33). Further, Ranbp2 loss in cones photoreceptors also elicits non-autonomous death of healthy rod photoreceptors (34), whereas asymptomatic mutations in human RANBP2 predispose the basal ganglia to acute necrotic damage (e.g. encephalopathy) upon exposure to various infectious agents (35-37). A parsimonious model of the multifold activities of multimodular Ranbp2 arises from structure-function analyses of Ranbp2, whereby the dynamic recruitme...

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“…An example of RTKs being a target for ocular pharmacology are the vascular endothelin growth factor (VEGF) receptor, where overstimulation of the receptor signals for the formation of abnormal blood vessel growth observed in wet age-related macular degeneration (AMD) or diabetic macular edema (Davuluri et al 2009;Triantafylla et al 2014;Witmer et al 2002). Cytokine receptors do not have kinase enzymatic activity itself and therefore need the use of intracellular tyrosine kinases such as JAK to phosphorylate the receptor itself as well as other proteins (Patel et al 2013). GCs are similar to RTKs and are part of the G protein-signaling cascade where they synthesize cyclic GMP from GTP (Gileadi 2014).…”

Section: Kinase-linked Receptorsmentioning

confidence: 99%

Principles of Ocular Pharmacology

Park

Ellis

Mueller

et al. 2016

Handbook of Experimental Pharmacology

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Recently, in a poll by Research America, a significant number of individuals placed losing their eyesight as having the greatest impact on their lives more so than other conditions, such as limb loss or memory loss. When they were also asked to rank which is the worst disease that could happen to them, blindness was ranked first by African-Americans and second by Caucasians, Hispanics, and Asians. Therefore, understanding the mechanisms of disease progression in the eye is extremely important if we want to make a difference in people's lives. In addition, developing treatment programs for these various diseases that could affect our eyesight is also critical. One of the most effective treatments we have is in the development of specific drugs that can be used to target various components of the mechanisms that lead to ocular disease. Understanding basic principles of the pharmacology of the eye is important if one seeks to develop effective treatments. As our population ages, the incidence of devastating eye diseases increases. It has been estimated that more than 65 million people suffer from glaucoma worldwide (Quigley and Broman. Br J Ophthalmol 90:262-267, 2006). Add to this the debilitating eye diseases of age-related macular degeneration, diabetic retinopathy, and cataract, the number of people effected exceeds 100 million. This chapter focuses on ocular pharmacology with specific emphasis on basic principles and outlining where in the various ocular sites are drug targets currently in use with effective drugs but also on future drug targets.

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Signal transducer and activator of transcription 3 (STAT3) signaling in retinal pigment epithelium cells

Cited by 14 publications

References 43 publications

Tear film proteome in age-related macular degeneration

Tear film proteome in age-related macular degeneration

Selective Impairment of a Subset of Ran-GTP-binding Domains of Ran-binding Protein 2 (Ranbp2) Suffices to Recapitulate the Degeneration of the Retinal Pigment Epithelium (RPE) Triggered by Ranbp2 Ablation

Principles of Ocular Pharmacology

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