This project investigates cell-cycle regulation in proliferating, quiescing, and differentiating lens cells through the studies of proto-oncogenes, cyclins, and cyclin-dependent kinases (cdks). We have established that cyclin B/p34cdc2 is present in embryonic rat lens fiber cells and that kinase activity associated with this complex peaks during denucleation of the primary lens fiber cells. To test whether cyclin B/p34cdc2 plays a causal role in fiber cell denucleation, we have used crystallin promoter constructs to overexpress proteins that will block p34cdc2 activity in lens fiber cells. Three lines overexpressing Wee1 protein in lens fibers have been bred to homozygosity and are currently being analyzed. Related studies have demonstrated that lens fiber cells lack p130/E2F complexes, which normally repress the expression of p34cdc2 in noncycling cells. A complete study of cdks has shown that lens fiber cells contain other active cdks, including p35/cdk5, which was previously thought to be brain specific. A second area of intense study is the regulation of proto-oncogene expression and cell proliferation in lens epithelial cells by 12(S)HETE, a lipoxygenase metabolite of arachidonic acid. Studies designed to probe the mechanism of 12(S)HETE action have demonstrated that 12(S)HETE is required to couple activation of receptor tyrosine kinase to activation of protein kinase C (PKC). Animal studies are planned to evaluate the potential of lipoxygenase inhibitors for controlling lens epithelial cell proliferation during posterior capsule opacification.
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