Decreased Expression of Ribosomal Proteins in Human Age-Related Cataract

Identification of genes with expression levels that are altered in age-related cataract relative to normal lenses points to those protective and regulatory processes important in the maintenance of lens transparency. To identify genes with expression levels that are altered in the presence of cataract, we compared the gene expression profiles of epithelia isolated from human lenses with age-related cataract and from normal human lenses. The lens epithelium contains the majority of metabolic enzymes present in the lens.1–3 It is the first part of the lens exposed to environmental insult.4,5 Metabolic communication between the lens epithelium and the underlying fiber cells has been demonstrated,6 and damage to the lens epithelium and its enzyme systems is associated with cataract formation.7–10 We have provided evidence that the human lens epithelium responds to the presence of age-related cataract through alterations in the levels of specific transcripts. These include decreased expression of protein phosphatase 2a regulatory subunit,11 increased expression of metallothionein IIa,11 and increased expression of osteonectin.12 In the present study, we have used RT-PCR differential display and semiquantitative RT-PCR to provide evidence that the large ribosomal subunit proteins L21, L15, L13a, and L7a exhibit decreased expression in cataract compared with normal human lenses. Ribosomal proteins are major constituents of ribosomes that catalyze protein synthesis in the cytoplasm.13 The eukaryotic ribosome is composed of a large (60S) and a small (40S) subunit consisting of three RNAs and 46 proteins and one RNA and 33 proteins, respectively.14 The catalytic functions specific to individual ribosomal proteins are largely unknown.14,15 Under normal conditions, ribosomal proteins are synthesized stoichiometrically with rRNA to produce equimolar amounts of RNA and protein. Under altered conditions, including events surrounding cellular growth and proliferation,16 the expression levels of ribosomal proteins are altered. For instance, the large ribosomal subunit proteins L3, L7, L8, L10, L23a, L27a, L36a, and L39 exhibit decreased expression during neuronal differentiation of human embryonic carcinoma cells, as do the levels of the small ribosomal subunit proteins.17 These alterations appear to be restricted to specific ribosomal proteins, because some ribosomal protein levels are altered, whereas others remain constant.18,19 Independent alterations in ribosomal protein synthesis suggest that individual ribosomal proteins have functions beyond the simple structural makeup of the ribosome or protein synthesis. For example, P0 and S3 possess endonuclease activity, suggesting that they may have DNA repair functions,20,21 and L7 can function as a coactivator of nuclear receptors.22 L7, S20, and S3a have been implicated in apoptosis.23–25 Altered ratios of ribosomal subunits are also associated with stage-specific tissue development.26 Several ribosomal proteins are known to be induced by agents associated with cataract including RPL13a, the synthesis of which is activated by exposure to UV irradiation, and RPL7, the synthesis of which is activated by exposure to UV irradiation, heat shock, or carcinogens.27 The present data provide evidence that the levels of specific ribosomal transcripts are decreased in age-related human cataract. Although we cannot distinguish that decreased ribosomal protein expression is a consequence of cataract or a response of the lens to cataract, the results suggest that regulation of protein synthesis and/or other functions mediated by ribosomes are associated with age-related cataract.