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Inhibition of FGF-Induced A-Crystallin Promoter Activity in Lens Epithelial Explants by TGFß

¹ From the Department of Anatomy and Histology and Institute for Biomedical Research, The University of Sydney, Australia; and the ² Department of Biological Science, Science University of Tokyo, Noda, Japan.

PURPOSE. Fibroblast growth factor (FGF) plays a key role in normal lens biology, and recent studies suggest that transforming growth factor (TGF)-ß is involved in the origin of certain forms of cataract. In the current study, the effects of FGF and TGFß on A-crystallin promoter activity were investigated.

METHODS. Rat lens epithelial explants were cultured with or without growth factors after transfecting with the firefly luciferase reporter gene driven by either the mouse A-crystallin promoter region or a control simian virus (SV)40 promoter.

RESULTS. FGF-2, at a concentration that induced lens fiber differentiation, strongly stimulated A-crystallin promoter activity in explants at 3 to 4 days of culture, whereas SV40 promoter control specimens showed no comparable increase. At lower concentrations of FGF, sufficient to induce cell proliferation but not differentiation, there was only a slight increase in A-crystallin promoter activity. Stimulation of A-crystallin promoter activity induced by the fiber-differentiating concentration of FGF was virtually abolished by as little as 25 pg/ml TGFß2, but the onset of fiber-specific ß-crystallin accumulation was not prevented at this concentration. Phase-contrast microscopy revealed overt cataractous changes only at concentrations of TGFß more than 25 pg/ml.

CONCLUSIONS. The stimulation of A-crystallin promoter activity by FGF is consistent with its role in inducing accumulation of crystallins in explants. The blocking effect of TGFß on this process, even at a concentration too low to induce obvious pathologic changes, indicates the potential for TGFß to disturb A-crystallin gene expression during early fiber differentiation.

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