Cancer-related diseases of the eye: the role of calcium and calcium-binding proteins

The eye provides unique opportunities to study complex biochemical pathways and to describe how components of these pathways contribute to the molecular basis of disease. In this article, the role of calcium-binding proteins in cancer-related diseases of the eye is reviewed. First, paraneoplastic syndromes, or so-called remote effects of cancer, arise from damage to tissues distant from any tumor or its metastases. Many of these syndromes are believed to be immune-mediated. Cancer-associated retinopathy (CAR), a blinding disease due to the degeneration of retinal photoreceptor cells, is one of the best characterized of the paraneoplastic syndromes. The CAR autoantigen has been identified as recoverin, a calcium-binding protein of the EF-hand superfamily. Its features as a calcium-binding protein, along with its function in photoreceptor cells and its role as the CAR autoantigen, are discussed. Next, unlike visual symptoms instigated by a distant tumor, ocular melanoma is the primary malignancy originating in the eye. ALG-2 encodes a pro-apoptotic calcium-binding protein that is down-regulated in ocular melanoma, thus providing these tumor cells with a selective advantage. In addition to background discussion of ALG-2, data describing the expression, cellular localization, and dimerization characteristics of ALG-2 in melanoma cells are presented. Biochemical studies of ALG-2 and its interactions with its target Alix/AIP1 also are presented. Finally, the function of ALG-2 in calcium-induced cell death is discussed. Additional calcium-binding proteins in retina and in ocular tumors are described in relation to different disease entities. Such proteins and their expression in the eye provide valuable examples bridging studies of protein chemistry, cellular function, and human disease.