{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Scortegagna M"],"funding":["NIDDK NIH HHS","NHLBI NIH HHS","NCI NIH HHS","PHS HHS"],"pagination":["e1004348"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4014425"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(5)"],"pubmed_abstract":["The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal isch"],"journal":["PLoS genetics"],"pubmed_title":["Fine tuning of the UPR by the ubiquitin ligases Siah1/2."],"pmcid":["PMC4014425"],"funding_grant_id":["R01 CA099961","NIH/NHLBI R01 HL052173","NIH/NCI R01 CA128814","P01 HL098053","P01 CA128814","NIH/NHLBI P01 HL098053","P30 CA030199","R01 HL052173","NIH/NCI R01 CA099961","NIH/NIDDK R37 DK042394","R37 DK042394","R01 DK088227","NIH/NIDDK R01DK088227"],"pubmed_authors":["Scortegagna M","Kim H","Kaufman RJ","Haddad G","Lau E","Li JL","Han J","Yao H","Brill LM","Ronai ZA","Bowtell D"],"additional_accession":[]},"is_claimable":false,"name":"Fine tuning of the UPR by the ubiquitin ligases Siah1/2.","description":"The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal isch","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 May","modification":"2025-04-22T02:49:10.048Z","creation":"2019-06-06T12:43:13Z"},"accession":"S-EPMC4014425","cross_references":{"pubmed":["24809345"],"doi":["10.1371/journal.pgen.1004348"]}}