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PMID:18230613
| Citation |
Romeo, GR and Kazlauskas, A (2008) Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1. J. Biol. Chem. 283:9595-605 |
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| Abstract |
Endothelial dysfunction plays a central role in diabetic vascular disease, but its molecular bases are not completely defined. We showed previously that the actin-binding protein proflin-1 was increased in the diabetic endothelium and that attenuated expression of profilin-1 protected against atherosclerosis. Also 7-ketocholesterol up-regulated profilin-1 in endothelial cells via transcriptional mechanisms. The present study addressed the pathways responsible for profilin-1 gene expression in 7-ketocholesterol-stimulated endothelial cells and in the diabetic aorta. In luciferase reporter assays, the response to 7-ketocholesterol within the 5'-flanking region of profilin-1 was dependent on a single STAT response element. In aortic endothelial cells, 7-ketocholesterol enhanced STAT3 activation, which required JAK2 and tyrosine 394 phosphorylation of oxysterol-binding protein-1. These changes were recapitulated in the aorta of diabetic rats. Also 7-ketocholesterol in cultured endothelial cells and diabetes in the aorta elicited the recruitment of STAT3 and relevant coregulatory factors to the oxysterol-responsive region of the profilin-1 promoter. These events were required for profilin-1 up-regulation. These studies identify a previously unrecognized oxysterol-binding protein-mediated mode of activation of STAT3 that controls the expression of the proatherogenic protein profilin-1 in response to 7-ketocholesterol and the diabetic milieu. |
| Links |
PubMed Online version:10.1074/jbc.M710092200 |
| Keywords |
Animals; Aorta/metabolism; Atherosclerosis/metabolism; Diabetes Mellitus, Experimental/metabolism; Endothelial Cells/metabolism; Janus Kinase 2/metabolism; Ketocholesterols/metabolism; Ketocholesterols/pharmacology; Male; Profilins/biosynthesis; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Receptors, Steroid/metabolism; STAT3 Transcription Factor/metabolism; Up-Regulation/drug effects |
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Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
part_of |
GO:0005634: nucleus |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
See also
References
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