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Weike Ji; αA-Crystallin Regulates p53-Mediated Signaling Pathway to Prevent Apoptosis of Lens Epithelial Cells and Cataractogenesis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1043.
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© ARVO (1962-2015); The Authors (2016-present)
Cataract is a major ocular disease that causes blindness in many developing countries. Studies from our laboratory and many others have shown that apoptosis plays a critical role in cataractogenesis. αA-crystallin (αA), a lens structure protein belongs to the small heat shock protein family that exerts anti-apoptotic functions. Mice deficient in αA (αA-/-) develops cataracts, and cell apoptosis was significant detected in αA-/- lens epithelium even before formation of obvious cataracts. However, the underlying molecular mechanism is largely unknown. The p53 protein plays a pivotal role in activating and integrating apoptosis pathways. The protein level of p53 is tight regulated by Ubiquitination. The purpose of the presented study is to explore the possible anti- apoptotic mechanism of αA through regulating the p53-mediated apoptotic signaling pathway.
Co-immunoprecipitation assays were used to investigate interactions between αA and p53. Reverse transcription polymerase chain reaction and Western-blot analysis were utilized to study the regulation of p53 signaling pathway in human lens epithelial cells (HLECs). MTT assay was used to evaluate cell viability under stressed conditions.
Our results showed that αA could directly bind to p53. Such interaction leads to significantly reduction of p53 level and activity. As a result, expression of its downstream target genes such as Bax was also downregulated. Mechanistically, αA enhances the interaction between p53 and its ubiquitin E3 ligase to promote p53 degradation.
These observations suggest that one of the mechanisms for αA to protect LECs from apoptosis, thus the lens pathology occurs through negative regulation of p53 functions.
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