Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis.
We previously discovered that systemic delivery of decorin for treatment of breast carcinoma xenografts induces paternally expressed gene 3 (Peg3), an imprinted gene encoding a zinc finger transcription factor postulated to function as a tumor suppressor. Here we found thatde novoexpression of Peg3 increased Beclin 1 promoter activity and protein expression. This process required the full-length Peg3 as truncated mutants lacking either the N-terminal SCAN domain or the zinc fingers failed to translocate to the nucleus and promote Beclin 1 transcription. Importantly, overexpression of Peg3 in endothelial cells stimulated autophagy and concurrently 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 simultaneously evoke autophagy in endothelial cells and attenuate angiogenesis.
From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Annabel
A
Torres
From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Maria A
MA
Gubbiotti
From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 renato.iozzo@jefferson.edu.
Renato V
RV
Iozzo
D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics*; D002460:Cell Line; D002465:Cell Movement; D058575:Decorin / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic; D019700:Thrombospondin 1 / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
C491997:BECN1 protein, human; D000071186:Beclin-1; D058575:Decorin; D051741:Kruppel-Like Transcription Factors; C490820:PEG3 protein, human; D019700:Thrombospondin 1
Beclin-1 (BECN1); angiogenesis; autophagy; cell biology; cell motility; decorin; proteoglycan