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Role of the Proteasome in TGF-ß Signaling in Lens Epithelial Cells

¹From the Departments of Biochemistry and Molecular Biology and ³Ophthalmology, the New Jersey Medical School, and the ²Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, the University of Medicine and Dentistry of New Jersey, Newark, New Jersey.

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-ß induced, cataract-associated gene activation in human lens cells.

METHODS. HLE B-3 cells were treated with TGF-ß, in combination with the proteasome inhibitors MG-132 or lactacystin. TGF-ß 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-ß induced the expression of -smooth muscle actin, fibronectin, and TGF-ß–inducible gene mRNA in HLE B-3 cells and primary cultured human lens cells from donor tissues. TGF-ß also induced a time-dependent decrease in the level of the Smad repressor SnoN. -Glutamyl-cysteine synthetase (-GCS) mRNA levels decreased in the presence of TGF-ß. Proteasome inhibitor cotreatment blocked the induction of -SMA mRNA, the loss of SnoN protein, the decrease in -GCS mRNA, and TGF-ß–induced apoptosis.

CONCLUSIONS. The HLE B-3 cell line and primary cultured human lens cells respond similarly to TGF-ß 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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