{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Eiselein L"],"funding":["NIA NIH HHS","NHLBI NIH HHS"],"pagination":["e0145523"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4699200"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(12)"],"pubmed_abstract":["Studies have suggested a link between the transforming growth factor beta 1 (TGF-?1) signaling cascade and the stress-inducible activating transcription factor 3 (ATF3). We have demonstrated that triglyceride-rich lipoproteins (TGRL) lipolysis products activate MAP kinase stress associated JNK/c-Jun pathways resulting in up-regulation of ATF3, pro-inflammatory genes and induction of apoptosis in human aortic endothelial cells. Here we demonstrate increased release of active TGF-? at 15 min, phosphorylation of Smad2 and translocation of co-Smad4 from cytosol to nucleus after a 1.5 h treatment with lipolysis products. Activation and translocation of Smad2 and 4 was blocked by addition of SB431542 (10 ?M), a specific inhibitor of TGF-?-activin receptor ALKs 4, 5, 7. Both ALK receptor inhibition and anti TGF-?1 antibody prevented lipolysis product induced up-regulation of ATF3 mRNA and protein. ALK inhibition prevented lipolysis product-induced nuclear accumulation of ATF3. ALKs 4, 5, 7 inhibition also prevented phosphorylation of c-Jun and TGRL lipolysis product-induced p53 and caspase-3 protein expression. These findings demonstrate that TGRL lipolysis products cause release of active TGF-? and lipolysis product-induced apoptosis is dependent on TGF-? signaling. Furthermore, signaling through the stress associated JNK/c-Jun pathway is dependent on TGF-? signaling suggesting that TGF-? signaling is necessary for nuclear accumulation of the ATF3/cJun transcription complex and induction of pro-inflammatory responses."],"journal":["PloS one"],"pubmed_title":["TGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-? Receptor Pathway in Human Aortic Endothelial Cells."],"pmcid":["PMC4699200"],"funding_grant_id":["AG039094","R01 AG039094","R01 HL055667","HL55667","R01 AG045541"],"pubmed_authors":["Nyunt T","Wilson DW","Lame MW","Eiselein L","Rutledge JC","Ng KF","Aung HH"],"additional_accession":[]},"is_claimable":false,"name":"TGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-? Receptor Pathway in Human Aortic Endothelial Cells.","description":"Studies have suggested a link between the transforming growth factor beta 1 (TGF-?1) signaling cascade and the stress-inducible activating transcription factor 3 (ATF3). We have demonstrated that triglyceride-rich lipoproteins (TGRL) lipolysis products activate MAP kinase stress associated JNK/c-Jun pathways resulting in up-regulation of ATF3, pro-inflammatory genes and induction of apoptosis in human aortic endothelial cells. Here we demonstrate increased release of active TGF-? at 15 min, phosphorylation of Smad2 and translocation of co-Smad4 from cytosol to nucleus after a 1.5 h treatment with lipolysis products. Activation and translocation of Smad2 and 4 was blocked by addition of SB431542 (10 ?M), a specific inhibitor of TGF-?-activin receptor ALKs 4, 5, 7. Both ALK receptor inhibition and anti TGF-?1 antibody prevented lipolysis product induced up-regulation of ATF3 mRNA and protein. ALK inhibition prevented lipolysis product-induced nuclear accumulation of ATF3. ALKs 4, 5, 7 inhibition also prevented phosphorylation of c-Jun and TGRL lipolysis product-induced p53 and caspase-3 protein expression. These findings demonstrate that TGRL lipolysis products cause release of active TGF-? and lipolysis product-induced apoptosis is dependent on TGF-? signaling. Furthermore, signaling through the stress associated JNK/c-Jun pathway is dependent on TGF-? signaling suggesting that TGF-? signaling is necessary for nuclear accumulation of the ATF3/cJun transcription complex and induction of pro-inflammatory responses.","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015","modification":"2021-02-20T19:21:22Z","creation":"2019-03-26T22:56:47Z"},"accession":"S-EPMC4699200","cross_references":{"pubmed":["26709509"],"doi":["10.1371/journal.pone.0145523"]}}