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Matthew R. Hosler, Shuh-Tuan Wang-Su, B. J. Wagner; Role of the Proteasome in TGF-β Signaling in Lens Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2006;47(5):2045-2052. doi: 10.1167/iovs.05-0650.
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purpose. The durability of the ubiquitin proteasome pathway in the mammalian lens makes this enzyme system a potential contributor to certain cataracts and posterior capsular opacification (PCO). The present study addresses proteasome involvement in TGF-β induced, cataract-associated gene activation in human lens cells.
methods. HLE B-3 cells were treated with TGF-β, in combination with the proteasome inhibitors MG-132 or lactacystin. TGF-β target gene expression was measured by semiquantitative RT-PCR. Annexin-FITC staining and flow cytometry were used to assess apoptosis levels. Western blot analyses were performed with anti-SnoN and anti-Smad2 antibodies.
results. TGF-β induced the expression of α-smooth muscle actin, fibronectin, and TGF-β–inducible gene mRNA in HLE B-3 cells and primary cultured human lens cells from donor tissues. TGF-β also induced a time-dependent decrease in the level of the Smad repressor SnoN. γ-Glutamyl-cysteine synthetase (γ-GCS) mRNA levels decreased in the presence of TGF-β. Proteasome inhibitor cotreatment blocked the induction of α-SMA mRNA, the loss of SnoN protein, the decrease in γ-GCS mRNA, and TGF-β–induced apoptosis.
conclusions. The HLE B-3 cell line and primary cultured human lens cells respond similarly to TGF-β treatments by activating cataract-related gene expression. This response in both of these model systems is blocked by inhibiting the proteasome. This suggests that the proteasome can mediate cataract and PCO-associated changes and therefore is a novel target of medical therapy.
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