The Role of Paternally Expressed Gene 3 in Regulating Autophagy and Angiogenesis
The imprinted paternally expressed gene 3 (Peg3) encodes a zinc finger transcription factor postulated to function as a tumor suppressor. We recently found that Peg3 is critical for endothelial cell autophagy evoked by activation of vascular endothelial growth factor receptor 2 by the small leucine-rich proteoglycan, decorin. Here we discovered that de novo expression of Peg3 increased Beclin 1 promoter activity and protein expression in a concentration-dependent manner contingent upon the full–length protein, instead of a particular domain. Indeed truncation mutants lacking the N-terminal SCAN domain or the zinc fingers failed to translocate to the nucleus for BECN1 induction. Importantly, overexpression of Peg3 in endothelial cells promoted autophagy as shown by the increase in Beclin 1 concurrent formation of LC3 positive autophagosomes. In addition, Peg3 evoked autophagic flux in endothelial cells as noted by the conversion of LC3-I to LC3-II. Overexpression of Peg3 also inhibited endothelial cell migration and evasion from a 3D matrix. Mechanistically, we found that Peg3 induced the secretion of the powerful angiostatic glycoprotein, Thrombospondin-1, independently of Beclin 1 transcriptional induction. Thus, we provide a new mechanism whereby Peg3 can evoke autophagy in endothelial cells and attenuate angiogenesis.
Torres, Annabel, "The Role of Paternally Expressed Gene 3 in Regulating Autophagy and Angiogenesis" (2016). ProQuest ETD Collection - Thomas Jefferson University. AAI10244646.