Arizona Health Sciences

Endoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy.

TitleEndoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy.
Publication TypeJournal Article
Year of Publication2015
AuthorsPan CC, Kumar S, Shah N, Bloodworth JC, Hawinkels LJAC, Mythreye K, Hoyt DG, Lee NY
JournalJ Biol Chem
Volume290
Issue24
Pagination14884-92
Date Published2015 Jun 12
ISSN1083-351X
KeywordsAnimals, Apoptosis Regulatory Proteins, Autophagy, Base Sequence, Beclin-1, Cells, Cultured, Chromatin Immunoprecipitation, DNA Primers, Endoglin, Endothelium, Intracellular Signaling Peptides and Proteins, Mice, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Smad2 Protein
Abstract

Autophagy is the targeted degradation of proteins and organelles critical for homeostasis and cell survival. Transforming growth factor β (TGF-β) differentially regulates autophagy in a context-specific manner, although the precise intracellular mechanisms remain less clear. Importantly, how TGF-β controls autophagic responses in endothelial cells (EC) during angiogenesis is unknown. Here we identified endoglin, an EC-specific TGF-β co-receptor essential for angiogenesis, as a key determinant of autophagy. Among the two opposing TGF-β Smad pathways in the EC system (Smad1/5/8 and Smad2/3), we found Smad2 as the major transcriptional regulator of autophagy that targets beclin1 (BECN1) gene expression. Smad2, but not Smad3, acts as a repressor upstream of the BECN1 promoter region. Overall, endoglin promotes autophagy by impeding Smad2 transcriptional repressor activity. Notably, increased beclin1 levels upon Smad2 knockdown directly correlated with enhanced autophagy during angiogenesis. Taken together, these results establish endoglin as a critical mediator of autophagy and demonstrate a new transcriptional mechanism by which Smad2 inhibits angiogenesis.

DOI10.1074/jbc.M114.630178
Alternate JournalJ. Biol. Chem.
PubMed ID25931117
PubMed Central IDPMC4463436
Grant ListP20 GM109091 / GM / NIGMS NIH HHS / United States
R01 CA178443 / CA / NCI NIH HHS / United States
CA178443 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
Nam Lee, Ph.D.