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1 From the Department of Cell Biology 2 Immunology, The Scripps Research Institute, La Jolla, California 3 Jules Stein Eye Institute at University of California, Los Angeles.
PURPOSE. To characterize the extracellular signal-regulated kinase (ERK) pathway in the lens and to try to understand how this pathway contributes to lens function and cataractogenesis.
METHODS. The members of the ERK pathway in the lens were examined by Western
blotting, immunohistochemical staining, and kinase assay. A
gain-of-function approach was used to perturb the ERK pathway in the
lenses of transgenic mice via expression of a constitutively active
mutant of the mitogen-activated protein kinase kinase 1 (MEK1(E)), the
direct upstream kinase of the ERK1 and ERK2 kinases, under the
A-crystallin promoter.
RESULTS. The presence of an active ERK pathway was found in lens epithelial cells and in differentiating fibers. Transgenic mice that expressed MEK1(E) developed postnatal cataracts as well as macrophthalmia. Distinct morphologic alterations, such as lens enlargement, swelling fiber cells, enlarged extracellular space, and vacuole formation, were observed in the lenses of these transgenic mice. A significant increase in the glucose transporter 1 (GLUT1) level, as well as in the glucose level, was detected in the lens.
CONCLUSIONS. The MAP kinase pathway is involved in the regulation of glucose metabolism and balance in the mouse lens. Moreover, the alteration of MAP kinase activity in the lens is sufficient to cause cataract formation with enlarged extracellular space and vacuoles in the differentiating fibers. This transgenic mouse may provide a useful model for understanding the mechanism(s) for some aspects of human cataracts.
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