The roles of mouse double minute 2 (MDM2) oncoprotein in ocular diseases: A review

Mouse double minute 2 (MDM2), an E3 ubiquitin ligase and the primary negative regulator of the tumor suppressor p53, cooperates with its structural homolog MDM4/MDMX to control intracellular p53 level. In turn, overexpression of p53 upregulates and forms an autoregulatory feedback loop with MDM2. The MDM2-p53 axis plays a pivotal role in modulating cell cycle control and apoptosis. MDM2 itself is regulated by the PI3K-AKT and RB-E2F-ARF pathways. While amplification of the MDM2 gene or overexpression of MDM2 (due to MDM2 SNP T309G, for instance) is associated with various malignancies, numerous studies have shown that MDM2/p53 alterations may also play a part in the pathogenetic process of certain ocular disorders. These include cancers (retinoblastoma, uveal melanoma), fibrocellular proliferative diseases (proliferative vitreoretinopathy, pterygium), neovascular diseases, degenerative diseases (cataract, primary open-angle glaucoma, age-related macular degeneration) and infectious/inflammatory diseases (trachoma, uveitis). In addition, MDM2 is implicated in retinogenesis and regeneration after optic nerve injury. Anti-MDM2 therapy has shown potential as a novel approach to treating these diseases. Despite major safety concerns, there are high expectations for the clinical value of reformative MDM2 inhibitors. This review summarizes important findings about the role of MDM2 in ocular pathologies and provides an overview of recent advances in treating these diseases with anti-MDM2 therapies.