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Cited by 20TGF-β signaling in diseasesRetinal Diseases and TreatmentsRetinal Development and Disorders

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Proteotoxic Stress Desensitizes TGF-beta Signaling Through Receptor Downregulation in Retinal Pigment Epithelial Cells

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Tan, X., Chen, C., Zhu, Y., Deng, J., Qiu, X., Huang, S., Shang, F., Cheng, B., Liu, Y.·2017·Current Molecular Medicine
DOI 10.2174/1566524017666170619113435PMC PMC5688417
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Abstract

BACKGROUND: Proteotoxic stress and transforming growth factor (TGFβ)- induced epithelial-mesenchymal transition (EMT) are two main contributors of intraocular fibrotic disorders, including proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). However, how these two factors communicate with each other is not well-characterized. OBJECTIVE: The aim was to investigate the regulatory role of proteotoxic stress on TGFβ signaling in retinal pigment epithelium. METHODS: ARPE-19 cells and primary human retinal pigment epithelial (RPE) cells were treated with proteasome inhibitor MG132 and TGFβ. Cell proliferation was analyzed by CCK-8 assay. The levels of mesenchymal markers α-SMA, fibronectin, and vimentin were analyzed by real-time polymerase chain reaction (PCR), western blot, and immunofluorescence. Cell migration was analyzed by scratch wound assay. The levels of p-Smad2, total Smad2, p-extracellular signal-regulated kinase 1/2 (ERK1/2), total ERK1/2, p-focal adhesion kinase (FAK), and total FAK were analyzed by western blot. The mRNA and protein levels of TGFβ receptor-II (TGFβR-II) were measured by realtime PCR and western blot, respectively. RESULTS: MG132-induced proteotoxic stress resulted in reduced cell proliferation. MG132 significantly suppressed TGFβ-induced upregulation of α-SMA, fibronectin, and vimentin, as well as TGFβ-induced cell migration. The phosphorylation levels of Smad2, ERK1/2, and FAK were also suppressed by MG132. Additionally, the mRNA level and protein level of TGFβR-II decreased upon MG132 treatment. CONCLUSION: Proteotoxic stress suppressed TGFβ-induced EMT through downregulation of TGFβR-II and subsequent blockade of Smad2, ERK1/2, and FAK activation.

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  • Dysregulation of TGFβ activity results in microvascular dysfunction leading to white matter lesions.

    “Dysregulation of TGF𝛃 activity results in microvascular dysfunction leading to white matter lesions (577).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [577]

    The Introduction discusses blood-retinal barrier dysfunction and TGFβ signaling in retinal disease, but does not say that dysregulated TGFβ causes microvascular dysfunction or white matter lesions. Searches for white matter lesions and microvascular dysfunction found no passage making that causal claim; the References list includes a paper on TGFβ and microvascular homeostasis, but does not establish the claimed link. (LLM, conf=0.76)

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Metadata

Authors
Tan, X., Chen, C., Zhu, Y., Deng, J., Qiu, X., Huang, S., Shang, F., Cheng, B., & Liu, Y.
Affiliations
Sun Yat-sen University (CN)
Corresponding author
  • Cheng, B.
  • Liu, Y.
ORCID
Venue
Current Molecular Medicine
Publisher
Bentham Science Publishers Ltd.
Published
2017-10-11
Volume
17
Issue
3
Pages
189-199
ISSN
1566-5240 (ISSN-L)
DOI
10.2174/1566524017666170619113435
PMC
PMC5688417
OpenAlex
W2669848631
Cited by
20
References
1
Citations by year
2024: 2 · 2023: 3 · 2022: 2 · 2020: 7 · 2019: 1 · 2018: 3 · 2017: 2
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Current Molecular Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Sun Yat-sen University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
Keywords
proteotoxic stress, TGF-beta signaling, epithelial-mesenchymal transition, retinal pigment epithelium, TGFBR2, receptor down-regulation, Smad2, ERK1/2, focal adhesion kinase, cell proliferation, cell migration, proteasome inhibition, MG132, proliferative vitreoretinopathy, proliferative diabetic retinopathy, retinal fibrosis
MeSH terms
Receptor, Transforming Growth Factor-beta Type II, Cell Movement, Diabetic Retinopathy, Gene Expression Regulation, Humans, Leupeptins, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Vitreoretinopathy, Proliferative, MAP Kinase Signaling System, Proteasome Endopeptidase Complex, Cell Proliferation, Focal Adhesion Kinase 1, Smad2 Protein, Retinal Pigment Epithelium, Epithelial-Mesenchymal Transition, Primary Cell Culture

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