Cell cycle regulation in the lens: Proliferation, quiescence, apoptosis and differentiation

This review has considered the cell cycle as an ordered sequence of interacting biochemical events which allows the periodic replication and division of the cell. Key events in the cell cycle are known to be catalysed by a family of cyclin-dependent kinases and their regulatory subunits, the cyclins. A growing body of evidence supports the idea that changes in the expression or activity of specific members of the cyclin and cdk families may also play a role in quiescence, apoptosis and differentiation. The lens has proven to be an excellent tissue in which to explore the involvement of cyclins and cdks in these processes. In the lens, proliferating, quiescent and differentiating cells are spatially separated, making it possible to correlate the expression of particular cell cycle elements with the in vivo status of the cell. Lens specific promoters are available, allowing expression of particular cell cycle regulatory proteins to be manipulated in vivo. Finally, several in vitro systems have been developed that permit studies of lens epithelial cell proliferation, differentiation and death under defined conditions. Studies of growth factors and growth factor receptors in the lens have identified several that are able to promote growth in vitro, and progress is being made in determining the signal transduction pathways by which they exert their effects. Lipid mediators synthesized by the lens, such as PGE2 and 12(S)HETE, also seem to play a role in regulating lens cell proliferation. Studies of factors that regulate lens epithelial cell growth are of special clinical significance because of the postsurgical problems presented by lens epithelial cell proliferation following intra-occular lens implantation. Continued research in this area may provide a method to prevent the posterior capsule opacification that results from this uncontrolled cell growth. Other types of cataract, such as posterior subcapsular cataract and many hereditary cataracts, appear to involve defects in the differentiation of lens fiber cells. The rapid progress in determining the biochemical events underlying terminal differentiation promises to provide new insight into the etiology of such cataracts. Specific alterations of the cell cycle regulatory apparatus may play an important role in lens fiber differentiation. Two G1 cyclins, D1 and D2, and the cyclin dependent kinase, cdks, are expressed at high levels during the early stages of differentiation. A specific inhibitor of cdk4, p57(Kip2) is likely to be important in preventing DNA synthesis. The G2 cyclin, cyclin B, is also expressed in lens fiber cells and forms an active complex with cdc2, the kinase which catalyses events associated with mitosis, such as nuclear envelope breakdown and chromosomal condensation. The expression and activation of cyclin B/cdc2 in the absence of DNA synthesis is also characteristic of certain apoptotic cells, raising the possibility that terminal differentiation of lens fiber cells may be an arrested or altered form of apoptosis.