{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:06:43Z","timestamp":1789416403228,"version":"build-2803163510"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:00:00Z","timestamp":1774656000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":40,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["MR 3226\/4-1"],"award-info":[{"award-number":["MR 3226\/4-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR353\/1-471011418"],"award-info":[{"award-number":["TRR353\/1-471011418"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Regulated in development and DNA damage response-1 (REDD1\/DDIT4) is induced in response to environmental stress to restrain the mechanistic target of rapamycin complex 1 (mTORC1) signaling as an adaptive strategy to restore cellular homeostasis. Interestingly, REDD1\/DDIT4 expression is upregulated in several tumor types including colorectal cancer, suggesting it may have a role in tumourigenesis. Here, we report that activating transcription factor 4 (ATF4)-dependent REDD1\/DDIT4 expression is required for survival of colon tumor cells undergoing endoplasmic reticulum (ER) stress through the modulation of TRAILR2\/DR5 gene expression. Our findings further demonstrate that resistance to ER stress-induced apoptosis in multicellular tumor spheroids (MCTS) is associated with constitutive expression of REDD1\/DDIT4 and diminished mTORC1 activity. CRISPR\/Cas9-mediated deletion of REDD1\/DDIT4 markedly increases TRAILR2\/DR5 expression and enhances apoptosis in spheroids exposed to ER stress. Interestingly, RNA sequencing analysis reveals that the loss of the transcriptional regulator EVI-1\/MECOM in cells deficient in REDD1\/DDIT4 amplifies the ER stress-induced upregulation of TRAILR2\/DR5, leading to enhanced apoptosis. In summary, our findings underscore the crucial role of REDD1\/DDIT4 in regulating TRAILR2\/DR5-induced caspase-8 activation and apoptosis under chronic ER stress, by inhibiting mTORC1 activity and promoting EVI-1\/MECOM-mediated suppression of TRAILR2\/DR5 gene expression.<\/jats:p>","DOI":"10.1038\/s41419-026-08648-7","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T17:35:33Z","timestamp":1774719333000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["REDD1\/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2\/DR5 in cancer cells"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7256-732X","authenticated-orcid":false,"given":"Roc\u00edo","family":"Mora-Molina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2450-3337","authenticated-orcid":false,"given":"Younes","family":"El Yousfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrin","family":"Hagenlocher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Fern\u00e1ndez-Farr\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6149-9261","authenticated-orcid":false,"given":"Markus","family":"Rehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1267-2619","authenticated-orcid":false,"given":"Carmen","family":"Palacios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Christophorou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9351-9690","authenticated-orcid":false,"given":"Abelardo","family":"L\u00f3pez-Rivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"8648_CR1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41568-020-00312-2","volume":"21","author":"X Chen","year":"2021","unstructured":"Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021;21:71\u201388.","journal-title":"Nat Rev Cancer"},{"key":"8648_CR2","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/332462a0","volume":"332","author":"Y Kozutsumi","year":"1988","unstructured":"Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature. 1988;332:462\u20134.","journal-title":"Nature"},{"key":"8648_CR3","doi-asserted-by":"publisher","first-page":"10631","DOI":"10.1158\/0008-5472.CAN-07-1705","volume":"67","author":"M Moenner","year":"2007","unstructured":"Moenner M, Pluquet O, Bouchecareilh M, Chevet E. Integrated endoplasmic reticulum stress responses in cancer. Cancer Res. 2007;67:10631\u20134.","journal-title":"Cancer Res"},{"key":"8648_CR4","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/nrm2199","volume":"8","author":"D Ron","year":"2007","unstructured":"Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519\u201329.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"8648_CR5","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1126\/science.1209038","volume":"334","author":"P Walter","year":"2011","unstructured":"Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081\u20136.","journal-title":"Science"},{"key":"8648_CR6","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/ncb0311-184","volume":"13","author":"I Tabas","year":"2011","unstructured":"Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13:184\u201390.","journal-title":"Nat Cell Biol"},{"key":"8648_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-017-0164-7","volume":"9","author":"A Cano-Gonzalez","year":"2018","unstructured":"Cano-Gonzalez A, Mauro-Lizcano M, Iglesias-Serret D, Gil J, Lopez-Rivas A. Involvement of both caspase-8 and Noxa-activated pathways in endoplasmic reticulum stress-induced apoptosis in triple-negative breast tumor cells. Cell Death Dis. 2018;9:134.","journal-title":"Cell Death Dis"},{"key":"8648_CR8","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1254312","volume":"345","author":"M Lu","year":"2014","unstructured":"Lu M, Lawrence DA, Marsters S, Acosta-Alvear D, Kimmig P, Mendez AS, et al. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science. 2014;345:98\u2013101.","journal-title":"Science"},{"key":"8648_CR9","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.1158\/0008-5472.CAN-13-1747","volume":"74","author":"R Martin-Perez","year":"2014","unstructured":"Martin-Perez R, Palacios C, Yerbes R, Cano-Gonzalez A, Iglesias-Serret D, Gil J, et al. Activated ERBB2\/HER2 licenses sensitivity to apoptosis upon endoplasmic reticulum stress through a PERK-dependent pathway. Cancer Res. 2014;74:1766\u201377.","journal-title":"Cancer Res"},{"key":"8648_CR10","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1128\/MCB.21.4.1249-1259.2001","volume":"21","author":"KD McCullough","year":"2001","unstructured":"McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21:1249\u201359.","journal-title":"Mol Cell Biol"},{"key":"8648_CR11","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04574-6","volume":"13","author":"R Mora-Molina","year":"2022","unstructured":"Mora-Molina R, Stohr D, Rehm M, Lopez-Rivas A. cFLIP downregulation is an early event required for endoplasmic reticulum stress-induced apoptosis in tumor cells. Cell Death Dis. 2022;13:111.","journal-title":"Cell Death Dis"},{"key":"8648_CR12","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1016\/j.cell.2007.04.027","volume":"129","author":"H Puthalakath","year":"2007","unstructured":"Puthalakath H, O\u2019Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129:1337\u201349.","journal-title":"Cell"},{"key":"8648_CR13","doi-asserted-by":"publisher","first-page":"45495","DOI":"10.1074\/jbc.M406933200","volume":"279","author":"H Yamaguchi","year":"2004","unstructured":"Yamaguchi H, HG Wang. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 2004;279:45495\u2013502.","journal-title":"J Biol Chem"},{"key":"8648_CR14","doi-asserted-by":"crossref","unstructured":"Lam M, Marsters SA, Ashkenazi A & Walter P. Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress. Elife 2020;9:e52291.","DOI":"10.7554\/eLife.52291"},{"key":"8648_CR15","doi-asserted-by":"publisher","first-page":"ra68","DOI":"10.1126\/scisignal.2005103","volume":"7","author":"MD Dennis","year":"2014","unstructured":"Dennis MD, Coleman CS, Berg A, Jefferson LS, Kimball SR. REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling. Sci Signal. 2014;7:ra68.","journal-title":"Sci Signal"},{"key":"8648_CR16","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1038\/ncb847","volume":"4","author":"X Gao","year":"2002","unstructured":"Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol. 2002;4:699\u2013704.","journal-title":"Nat Cell Biol"},{"key":"8648_CR17","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/ncb839","volume":"4","author":"K Inoki","year":"2002","unstructured":"Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4:648\u201357.","journal-title":"Nat Cell Biol"},{"key":"8648_CR18","doi-asserted-by":"publisher","first-page":"13571","DOI":"10.1073\/pnas.202476899","volume":"99","author":"AR Tee","year":"2002","unstructured":"Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA. 2002;99:13571\u20136.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8648_CR19","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","volume":"115","author":"K Inoki","year":"2003","unstructured":"Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577\u201390.","journal-title":"Cell"},{"key":"8648_CR20","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.molcel.2007.12.023","volume":"29","author":"U Ozcan","year":"2008","unstructured":"Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell. 2008;29:541\u201351.","journal-title":"Mol Cell"},{"key":"8648_CR21","doi-asserted-by":"publisher","first-page":"4675","DOI":"10.1073\/pnas.0907705107","volume":"107","author":"P Horak","year":"2010","unstructured":"Horak P, Crawford AR, Vadysirisack DD, Nash ZM, DeYoung MP, Sgroi D, et al. Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis. Proc Natl Acad Sci USA. 2010;107:4675\u201380.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8648_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8014","volume":"6","author":"S Qiao","year":"2015","unstructured":"Qiao S, Dennis M, Song X, Vadysirisack DD, Salunke D, Nash Z, et al. A REDD1\/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity. Nat Commun. 2015;6:7014.","journal-title":"Nat Commun"},{"key":"8648_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-07182-z","volume":"7","author":"F Pastor","year":"2017","unstructured":"Pastor F, Dumas K, Barthelemy MA, Regazzetti C, Druelle N, Peraldi P, et al. Implication of REDD1 in the activation of inflammatory pathways. Sci Rep. 2017;7:7023.","journal-title":"Sci Rep"},{"key":"8648_CR24","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.1101\/gad.1256804","volume":"18","author":"J Brugarolas","year":"2004","unstructured":"Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1\/TSC2 tumor suppressor complex. Genes Dev. 2004;18:2893\u2013904.","journal-title":"Genes Dev"},{"key":"8648_CR25","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1101\/gad.1617608","volume":"22","author":"MP DeYoung","year":"2008","unstructured":"DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1\/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;22:239\u201351.","journal-title":"Genes Dev"},{"key":"8648_CR26","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1101\/gad.335166.119","volume":"34","author":"S Qiao","year":"2020","unstructured":"Qiao S, Koh SB, Vivekanandan V, Salunke D, Patra KC, Zaganjor E, et al. REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors. Genes Dev. 2020;34:751\u201366.","journal-title":"Genes Dev"},{"key":"8648_CR27","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1016\/j.celrep.2017.01.051","volume":"18","author":"G Di Conza","year":"2017","unstructured":"Di Conza G, Trusso Cafarello S, Loroch S, Mennerich D, Deschoemaeker S, Di Matteo M, et al. The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1alpha levels and colorectal cancer cell survival under hypoxia. Cell Rep. 2017;18:1699\u2013712.","journal-title":"Cell Rep"},{"key":"8648_CR28","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1038\/s41418-021-00771-6","volume":"28","author":"E Backx","year":"2021","unstructured":"Backx E, Wauters E, Baldan J, Van Bulck M, Michiels E, Heremans Y, et al. MECOM permits pancreatic acinar cell dedifferentiation avoiding cell death under stress conditions. Cell Death Differ. 2021;28:2601\u201315.","journal-title":"Cell Death Differ"},{"key":"8648_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00457-9","volume":"11","author":"C Birdwell","year":"2021","unstructured":"Birdwell C, Fiskus W, Kadia TM, DiNardo CD, Mill CP, Bhalla KN. EVI1 dysregulation: impact on biology and therapy of myeloid malignancies. Blood Cancer J. 2021;11:64.","journal-title":"Blood Cancer J"},{"key":"8648_CR30","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/leu.2012.211","volume":"27","author":"M Konantz","year":"2013","unstructured":"Konantz M, Andre MC, Ebinger M, Grauer M, Wang H, Grzywna S, et al. EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia. Leukemia. 2013;27:56\u201365.","journal-title":"Leukemia"},{"key":"8648_CR31","doi-asserted-by":"publisher","first-page":"2815","DOI":"10.1182\/blood.V97.9.2815","volume":"97","author":"K Izutsu","year":"2001","unstructured":"Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood. 2001;97:2815\u201322.","journal-title":"Blood"},{"key":"8648_CR32","doi-asserted-by":"publisher","first-page":"25834","DOI":"10.1074\/jbc.M102343200","volume":"276","author":"S Palmer","year":"2001","unstructured":"Palmer S, Brouillet JP, Kilbey A, Fulton R, Walker M, Crossley M, et al. Evi-1 transforming and repressor activities are mediated by CtBP co-repressor proteins. J Biol Chem. 2001;276:25834\u201340.","journal-title":"J Biol Chem"},{"key":"8648_CR33","doi-asserted-by":"publisher","first-page":"5129","DOI":"10.1093\/emboj\/17.17.5129","volume":"17","author":"J Turner","year":"1998","unstructured":"Turner J, Crossley M. Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators. EMBO J. 1998;17:5129\u201340.","journal-title":"EMBO J"},{"key":"8648_CR34","doi-asserted-by":"publisher","first-page":"4568","DOI":"10.1073\/pnas.0830998100","volume":"100","author":"M Grooteclaes","year":"2003","unstructured":"Grooteclaes M, Deveraux Q, Hildebrand J, Zhang Q, Goodman RH, Frisch SM. C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs. Proc Natl Acad Sci USA. 2003;100:4568\u201373.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8648_CR35","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/cdd.2009.140","volume":"17","author":"RC Kovi","year":"2010","unstructured":"Kovi RC, Paliwal S, Pande S, Grossman SR. An ARF\/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis. Cell Death Differ. 2010;17:513\u201321.","journal-title":"Cell Death Differ"},{"key":"8648_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2455-7","volume":"11","author":"B Ding","year":"2020","unstructured":"Ding B, Yuan F, Damle PK, Litovchick L, Drapkin R, Grossman SR. CtBP determines ovarian cancer cell fate through repression of death receptors. Cell Death Dis. 2020;11:286.","journal-title":"Cell Death Dis"},{"key":"8648_CR37","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.cmet.2016.09.008","volume":"24","author":"M Wenes","year":"2016","unstructured":"Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Perez R, Serneels J, et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 2016;24:701\u201315.","journal-title":"Cell Metab"},{"key":"8648_CR38","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","volume":"6","author":"HP Harding","year":"2000","unstructured":"Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6:1099\u2013108.","journal-title":"Mol Cell"},{"key":"8648_CR39","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1128\/MCB.23.4.1292-1303.2003","volume":"23","author":"MH Brush","year":"2003","unstructured":"Brush MH, Weiser DC, Shenolikar S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol. 2003;23:1292\u2013303.","journal-title":"Mol Cell Biol"},{"key":"8648_CR40","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1083\/jcb.153.5.1011","volume":"153","author":"I Novoa","year":"2001","unstructured":"Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153:1011\u201322.","journal-title":"J Cell Biol"},{"key":"8648_CR41","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/ncb2738","volume":"15","author":"J Han","year":"2013","unstructured":"Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15:481\u201390.","journal-title":"Nat Cell Biol"},{"key":"8648_CR42","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1016\/j.freeradbiomed.2009.01.015","volume":"46","author":"HO Jin","year":"2009","unstructured":"Jin HO, Seo SK, Woo SH, Kim ES, Lee HC, Yoo DH, et al. Activating transcription factor 4 and CCAAT\/enhancer-binding protein-beta negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress. Free Radic Biol Med. 2009;46:1158\u201367.","journal-title":"Free Radic Biol Med"},{"key":"8648_CR43","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.bbrc.2012.09.074","volume":"427","author":"SR Kimball","year":"2012","unstructured":"Kimball SR, Jefferson LS. Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2alpha phosphorylation, ATF4-dependent cascade. Biochem Biophys Res Commun. 2012;427:485\u20139.","journal-title":"Biochem Biophys Res Commun"},{"key":"8648_CR44","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.bbrc.2008.12.079","volume":"379","author":"ML Whitney","year":"2009","unstructured":"Whitney ML, Jefferson LS, Kimball SR. ATF4 is necessary and sufficient for ER stress-induced upregulation of REDD1 expression. Biochem Biophys Res Commun. 2009;379:451\u20135.","journal-title":"Biochem Biophys Res Commun"},{"key":"8648_CR45","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/nature17041","volume":"529","author":"M Wang","year":"2016","unstructured":"Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529:326\u201335.","journal-title":"Nature"},{"key":"8648_CR46","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1083\/jcb.200302084","volume":"162","author":"WX Zong","year":"2003","unstructured":"Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, Yuan J, et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol. 2003;162:59\u201369.","journal-title":"J Cell Biol"},{"key":"8648_CR47","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1016\/j.molcel.2016.02.023","volume":"61","author":"MA Hughes","year":"2016","unstructured":"Hughes MA, Powley IR, Jukes-Jones R, Horn S, Feoktistova M, Fairall L, et al. Co-operative and hierarchical binding of c-FLIP and caspase-8: a unified model defines how c-FLIP isoforms differentially control cell fate. Mol Cell. 2016;61:834\u201349.","journal-title":"Mol Cell"},{"key":"8648_CR48","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201949254","volume":"21","author":"LM Humphreys","year":"2020","unstructured":"Humphreys LM, Fox JP, Higgins CA, Majkut J, Sessler T, McLaughlin K, et al. A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis. EMBO Rep. 2020;21:e49254.","journal-title":"EMBO Rep"},{"key":"8648_CR49","doi-asserted-by":"publisher","first-page":"7993","DOI":"10.2147\/IJN.S146927","volume":"12","author":"M Millard","year":"2017","unstructured":"Millard M, Yakavets I, Zorin V, Kulmukhamedova A, Marchal S, Bezdetnaya L. Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening. Int J Nanomed. 2017;12:7993\u20138007.","journal-title":"Int J Nanomed"},{"key":"8648_CR50","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.pharmthera.2016.03.013","volume":"163","author":"S Nath","year":"2016","unstructured":"Nath S, Devi GR. Three-dimensional culture systems in cancer research: focus on tumor spheroid model. Pharm Ther. 2016;163:94\u2013108.","journal-title":"Pharm Ther"},{"key":"8648_CR51","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/nrm2236","volume":"8","author":"F Pampaloni","year":"2007","unstructured":"Pampaloni F, Reynaud EG, Stelzer EH. The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol. 2007;8:839\u201345.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"8648_CR52","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.1038\/s41418-020-0559-3","volume":"27","author":"D Stohr","year":"2020","unstructured":"Stohr D, Schmid JO, Beigl TB, Mack A, Maichl DS, Cao K, et al. Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids. Cell Death Differ. 2020;27:3037\u201352.","journal-title":"Cell Death Differ"},{"key":"8648_CR53","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.molcel.2018.06.038","volume":"71","author":"TK Chang","year":"2018","unstructured":"Chang TK, Lawrence DA, Lu M, Tan J, Harnoss JM, Marsters SA, et al. Coordination between two branches of the unfolded protein response determines apoptotic cell fate. Mol Cell. 2018;71:629\u201336.","journal-title":"Mol Cell"},{"key":"8648_CR54","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1126\/science.1146361","volume":"318","author":"JH Lin","year":"2007","unstructured":"Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007;318:944\u20139.","journal-title":"Science"},{"key":"8648_CR55","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1016\/j.celrep.2014.09.016","volume":"9","author":"AB Tam","year":"2014","unstructured":"Tam AB, Koong AC, Niwa M. IRE1 has distinct catalytic mechanisms for XBP1\/HAC1 splicing and RIDD. Cell Rep. 2014;9:850\u20138.","journal-title":"Cell Rep"},{"key":"8648_CR56","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1126\/science.287.5453.664","volume":"287","author":"F Urano","year":"2000","unstructured":"Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287:664\u20136.","journal-title":"Science"},{"key":"8648_CR57","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1038\/sj.embor.7400687","volume":"7","author":"Q Yang","year":"2006","unstructured":"Yang Q, Kim YS, Lin Y, Lewis J, Neckers L, Liu ZG. Tumour necrosis factor receptor 1 mediates endoplasmic reticulum stress-induced activation of the MAP kinase JNK. EMBO Rep. 2006;7:622\u20137.","journal-title":"EMBO Rep"},{"key":"8648_CR58","doi-asserted-by":"publisher","first-page":"fj201800413RR","DOI":"10.1096\/fj.201800413RR","volume":"32","author":"W Dai","year":"2018","unstructured":"Dai W, Miller WP, Toro AL, Black AJ, Dierschke SK, Feehan RP, et al. Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation. FASEB J. 2018;32:fj201800413RR.","journal-title":"FASEB J"},{"key":"8648_CR59","first-page":"301","volume":"8","author":"ML Mucenski","year":"1988","unstructured":"Mucenski ML, Taylor BA, Ihle JN, Hartley JW, Morse HC 3rd, et al. Identification of a common ecotropic viral integration site, Evi-1, in the DNA of AKXD murine myeloid tumors. Mol Cell Biol. 1988;8:301\u20138.","journal-title":"Mol Cell Biol"},{"key":"8648_CR60","doi-asserted-by":"publisher","first-page":"E2885","DOI":"10.1073\/pnas.1309310110","volume":"110","author":"EA Bard-Chapeau","year":"2013","unstructured":"Bard-Chapeau EA, Gunaratne J, Kumar P, Chua BQ, Muller J, Bard FA, et al. EVI1 oncoprotein interacts with a large and complex network of proteins and integrates signals through protein phosphorylation. Proc Natl Acad Sci USA. 2013;110:E2885\u20132894.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8648_CR61","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk9076","volume":"10","author":"D Pastoors","year":"2024","unstructured":"Pastoors D, Havermans M, Mulet-Lazaro R, Brian D, Noort W, Grasel J, et al. Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2. Sci Adv. 2024;10:eadk9076.","journal-title":"Sci Adv"},{"key":"8648_CR62","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.4161\/cc.4.11.2139","volume":"4","author":"LW Ellisen","year":"2005","unstructured":"Ellisen LW. Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle. 2005;4:1500\u20132.","journal-title":"Cell Cycle"},{"key":"8648_CR63","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1038\/s12276-023-01056-3","volume":"55","author":"JY Kim","year":"2023","unstructured":"Kim JY, Kwon YG, Kim YM. The stress-responsive protein REDD1 and its pathophysiological functions. Exp Mol Med. 2023;55:1933\u201344.","journal-title":"Exp Mol Med"},{"key":"8648_CR64","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1002\/cam4.198","volume":"3","author":"I Sinha","year":"2014","unstructured":"Sinha I, Allen JE, Pinto JT, Sinha R. Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia. Cancer Med. 2014;3:252\u201364.","journal-title":"Cancer Med"},{"key":"8648_CR65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-92720-z","volume":"11","author":"F Fattahi","year":"2021","unstructured":"Fattahi F, Saeednejad Zanjani L, Habibi Shams Z, Kiani J, Mehrazma M, Najafi M, et al. High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer. Sci Rep. 2021;11:13626.","journal-title":"Sci Rep"},{"key":"8648_CR66","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-01207-3","volume":"7","author":"JA Pinto","year":"2017","unstructured":"Pinto JA, Rolfo C, Raez LE, Prado A, Araujo JM, Bravo L, et al. In silico evaluation of DNA Damage Inducible Transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies. Sci Rep. 2017;7:1526.","journal-title":"Sci Rep"},{"key":"8648_CR67","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/cdd.2011.98","volume":"19","author":"H Kato","year":"2012","unstructured":"Kato H, Nakajima S, Saito Y, Takahashi S, Katoh R, Kitamura M. mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1-JNK pathway. Cell Death Differ. 2012;19:310\u201320.","journal-title":"Cell Death Differ"},{"key":"8648_CR68","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1002\/mc.21852","volume":"52","author":"X Deng","year":"2013","unstructured":"Deng X, Cao Y, Liu Y, Li F, Sambandam K, Rajaraman S, et al. Overexpression of Evi-1 oncoprotein represses TGF-beta signaling in colorectal cancer. Mol Carcinog. 2013;52:255\u201364.","journal-title":"Mol Carcinog"},{"key":"8648_CR69","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1002\/ijc.22083","volume":"119","author":"C Pena","year":"2006","unstructured":"Pena C, Garcia JM, Garcia V, Silva J, Dominguez G, Rodriguez R, et al. The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E-cadherin and vitamin D receptor in human colon carcinomas. Int J Cancer. 2006;119:2098\u2013104.","journal-title":"Int J Cancer"},{"key":"8648_CR70","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1046\/j.1365-2141.2001.02987.x","volume":"114","author":"U Vinatzer","year":"2001","unstructured":"Vinatzer U, Taplick J, Seiser C, Fonatsch C, Wieser R. The leukaemia-associated transcription factors EVI-1 and MDS1\/EVI1 repress transcription and interact with histone deacetylase. Br J Haematol. 2001;114:566\u201373.","journal-title":"Br J Haematol"},{"key":"8648_CR71","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1016\/j.febslet.2008.06.056","volume":"582","author":"D Spensberger","year":"2008","unstructured":"Spensberger D, Delwel R. A novel interaction between the proto-oncogene Evi1 and histone methyltransferases, SUV39H1 and G9a. FEBS Lett. 2008;582:2761\u20137.","journal-title":"FEBS Lett"},{"key":"8648_CR72","doi-asserted-by":"publisher","first-page":"6418","DOI":"10.1021\/bi800267f","volume":"47","author":"D Spensberger","year":"2008","unstructured":"Spensberger D, Vermeulen M, Le Guezennec X, Beekman R, van Hoven A, Bindels E, et al. Myeloid transforming protein Evi1 interacts with methyl-CpG binding domain protein 3 and inhibits in vitro histone deacetylation by Mbd3\/Mi-2\/NuRD. Biochemistry. 2008;47:6418\u201326.","journal-title":"Biochemistry"},{"key":"8648_CR73","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.bbamcr.2010.10.003","volume":"1813","author":"R Yerbes","year":"2011","unstructured":"Yerbes R, Palacios C, Reginato MJ, Lopez-Rivas A. Cellular FLIP(L) plays a survival role and regulates morphogenesis in breast epithelial cells. Biochim Biophys Acta. 2011;1813:168\u201378.","journal-title":"Biochim Biophys Acta"},{"key":"8648_CR74","doi-asserted-by":"publisher","first-page":"8957","DOI":"10.1128\/JVI.77.16.8957-8951.2003","volume":"77","author":"M Wiznerowicz","year":"2003","unstructured":"Wiznerowicz M, Trono D. Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol. 2003;77:8957\u201361.","journal-title":"J Virol"},{"key":"8648_CR75","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1042\/bj20020184","volume":"365","author":"C Ruiz-Ruiz","year":"2002","unstructured":"Ruiz-Ruiz C, Lopez-Rivas A. Mitochondria-dependent and -independent mechanisms in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis are both regulated by interferon-gamma in human breast tumour cells. Biochem J. 2002;365:825\u201332.","journal-title":"Biochem J"},{"key":"8648_CR76","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671\u20135.","journal-title":"Nat Methods"},{"key":"8648_CR77","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/nmeth.1226","volume":"5","author":"A Mortazavi","year":"2008","unstructured":"Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5:621\u20138.","journal-title":"Nat Methods"},{"key":"8648_CR78","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/nbt.1621","volume":"28","author":"C Trapnell","year":"2010","unstructured":"Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28:511\u20135.","journal-title":"Nat Biotechnol"},{"key":"8648_CR79","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.","journal-title":"Genome Biol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08648-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08648-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08648-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T08:04:02Z","timestamp":1778141042000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08648-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,28]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8648"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08648-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6111887\/v1","asserted-by":"object"}]},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,28]]},"assertion":[{"value":"26 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 March 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors disclose no potential conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All the methods were performed in accordance with the relevant guidelines and regulations. The experiments performed in this work did not use material that requires ethical approval.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"425"}}