Since Meg3 can interact with p53 directly (25,26,28), it is possible that the interaction between Meg3 and p53 could competitively prevent the binding of p53 to the promoters of these p53-regulated genes, although this mechanism itself cannot explain the selective induction of p53-regulated genes upon Meg3 or PTBP3 silencing

Since Meg3 can interact with p53 directly (25,26,28), it is possible that the interaction between Meg3 and p53 could competitively prevent the binding of p53 to the promoters of these p53-regulated genes, although this mechanism itself cannot explain the selective induction of p53-regulated genes upon Meg3 or PTBP3 silencing. a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets Letermovir for therapies to restore endothelial homeostasis. INTRODUCTION The vascular endothelium plays an important role in maintaining the proper functions of different organs. Endothelial dysfunction contributes to the pathogenesis of major chronic diseases such as obesity, diabetes and atherosclerosis (1C4). Different insults, such as chronic inflammatory disease states, oxidative stress, metabolic dysfunction and aging, promote endothelial dysfunction through transcriptional reprogramming (5C8). In response to these insults, DNA damage may ensue and adversely contribute to cardiovascular and metabolic disease (9C12). However, the molecular mechanisms and signaling events by which DNA damage regulates endothelial function are not completely understood. The cellular response to DNA damage involves the activation of multiple signaling cascades that orchestrate the appropriate repair of DNA damage with signaling events involved in apoptosis and proliferation (13,14). The DNA damage response (DDR) resulting from genotoxic, oxidative, and metabolic stress is controlled by three phosphoinositide 3-kinase (PI3K)-related kinases: Ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) (12,13). Formation of DNA double-strand breaks (DSB) is a severe type of DNA damage. ATM is vigorously activated following DSB and interacts with many downstream effectors including p53 (14). p53 protein is a stress- and DNA damage-responsive transcriptional factor that activates cell cycle arrest, DNA Letermovir repair, and apoptosis (15). High glucose or palmitic acid induces p53 expression in human endothelial cells (ECs) (16). Expression of p53 is also induced in vascular endothelium in mice fed a high-calorie diet (16). Inhibition of endothelial p53 attenuated metabolic abnormalities associated with dietary obesity (16). Deletion of p53 in the vascular endothelium reduced the number of apoptotic ECs in mice, and protects mice from cardiac dysfunction after pressure overload (17). Therefore, discovering new mechanisms by which p53 signaling regulates endothelial function may provide new targets for therapeutic intervention. Long non-coding RNAs (lncRNAs) are an important class of RNA transcripts that regulate gene expression and signal transduction. Changes in their expression and function contribute to the pathogenesis of a range of disease states (18C21). LncRNAs participate in several aspects of the DDR and regulate the expression of key components of related pathways (22,23). LncRNA maternally expressed gene 3 (Meg3) is an imprinted gene located at chromosome 12 in mice and chromosome 14 in humans (24). The role of Meg3 has been examined in different cell types including cancer cells, neurons, hepatocytes, cardiac fibroblasts, and ECs (25C30). Meg3 regulates p53 signaling in a cell-specific manner. Meg3 interacts with p53 in cancer cells and neurons to activate p53-mediated inhibition of cell proliferation and induction of apoptosis (25,27,28). In contrast, Meg3 interacts with p53 in cardiac fibroblasts exerting no effects on a p53 response, cell apoptosis, or proliferation (26). These studies also highlight that Meg3 may regulate CACN2 p53 signaling in a cell-specific manner. However, it remains unknown how Meg3 determines the transcriptional output of p53 signaling in the regulation of EC proliferation and apoptosis in response Letermovir to DNA damage. Moreover, Letermovir the reciprocal regulation of Meg3 and DNA damage remains poorly understood. In this study, we find that Meg3 cooperates with polypyrimidine tract binding protein 3.