摘要
Phosphorylation affects ubiquitination, stability, and activity of transcriptional factors, thus regulating various cellular functions. E2F transcriptional factor I （E2F1） regulates paternally expressed imprinted gene 10 （Peg10） expression, thereby promoting cell proliferation. However, the effect of E2FZ stability on PeglO expression and the molecular regulation of E2FZ stability by its phos- phorylation have not been well demonstrated. Here, we describe a new pathway in which phosphorylation of E2F1 by GSK3p increases E2FZ association with the deubiquitinating enzyme, ubiquitin-specific protease 11 （USPll）, which removes K63-1inked ubiquitin chains thereby preventing E2FZ degradation in the nuclei. Downregulation of USPlZ increases E2FZ ubiquitination and reduces E2F1 stability and protein levels, thereby decreasing PeglO mRNA levels. Physiologically, USPll depletion suppresses cell proliferation and wound healing in lung epithelial cells, and these effects are reversed by E2F1 and PEGIO overexpression. Thus, our study reveals a new molecular model that phosphorylation promotes substrate stability through increasing its associ- ation with a deubiquitinating enzyme. The data suggest that GSK3p and USPll act in concert to modulate E2FZ abundance and PEGIO expression in lung epithelial celts to affect cell wound healing. This study provides new therapeutic targets to lessen lung injury by improving lung epithelial cell repair and remodeling after injury.
