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J Biol Chem. 2015 Jun 12;290(24):14884-92. doi: 10.1074/jbc.M114.630178. Epub 2015 Apr 30.

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

Author information

1
From the Division of Pharmacology, College of Pharmacy.
2
Loyola University Medical Center, Loyola University, Maywood, Illinois 60153, and.
3
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
4
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
5
From the Division of Pharmacology, College of Pharmacy, Davis Heart and Lung Research Institute, and James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, lee.5064@osu.edu.

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.

KEYWORDS:

SMAD transcription factor; angiogenesis; autophagy; endothelial cell; transforming growth factor beta (TGF-β)

PMID:
25931117
PMCID:
PMC4463436
DOI:
10.1074/jbc.M114.630178
[Indexed for MEDLINE]
Free PMC Article

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