{"entity": "researcher", "timestamp": "2026-08-20T20:32:15.141Z", "family": "Hatzoglou", "given": "Maria", "initials": "M", "orcid": "0000-0003-2037-1231", "affiliations": ["Department of Genetics, Case Western Reserve University, Cleveland, OH, USA."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/3fbc5330f8c84c548a8472bb81cf77f3.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/3fbc5330f8c84c548a8472bb81cf77f3"}}, "publications": [{"entity": "publication", "iuid": "a312b3ce8eec4855b16873537f95a8bb", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a312b3ce8eec4855b16873537f95a8bb.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a312b3ce8eec4855b16873537f95a8bb"}}, "title": "Plasticity of the mammalian integrated stress response.", "authors": [{"family": "Chen", "given": "Chien-Wen", "initials": "CW", "orcid": "0000-0002-1214-4058", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/31bfc8f68c7f46c184b233efccd23651.json"}}, {"family": "Papadopoli", "given": "David", "initials": "D"}, {"family": "Szkop", "given": "Krzysztof J", "initials": "KJ"}, {"family": "Guan", "given": "Bo-Jhih", "initials": "BJ"}, {"family": "Alzahrani", "given": "Mohammed", "initials": "M", "orcid": "0000-0001-7291-5275", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2b8c5964a93e47eea6601cc9b13ae343.json"}}, {"family": "Wu", "given": "Jing", "initials": "J", "orcid": "0009-0000-5199-1199", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ac7a88e311aa495a93825a2a7065da88.json"}}, {"family": "Jobava", "given": "Raul", "initials": "R"}, {"family": "Asraf", "given": "Mais M", "initials": "MM"}, {"family": "Krokowski", "given": "Dawid", "initials": "D"}, {"family": "Vourekas", "given": "Anastasios", "initials": "A", "orcid": "0000-0002-1850-5635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/85a3939de7c341b084bb7293bfb505b9.json"}}, {"family": "Merrick", "given": "William C", "initials": "WC"}, {"family": "Komar", "given": "Anton A", "initials": "AA"}, {"family": "Koromilas", "given": "Antonis E", "initials": "AE", "orcid": "0000-0003-1972-0799", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7825afc7ac8942819083ce7c570b5508.json"}}, {"family": "Gorospe", "given": "Myriam", "initials": "M", "orcid": "0000-0001-5439-3434", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f959a00a1c6d406892d949aeafed5a4f.json"}}, {"family": "Payea", "given": "Matthew J", "initials": "MJ", "orcid": "0000-0002-1960-4563", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7127b888bae44cd59c2e1d60eff38366.json"}}, {"family": "Wang", "given": "Fangfang", "initials": "F"}, {"family": "Clayton", "given": "Benjamin L L", "initials": "BLL", "orcid": "0000-0001-9552-404X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7d27aa75b2e84ddf8c7ac065d22db7fd.json"}}, {"family": "Tesar", "given": "Paul J", "initials": "PJ", "orcid": "0000-0003-1532-3155", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2126dba093aa4bfd8ed62c630333452e.json"}}, {"family": "Schaffer", "given": "Ashleigh", "initials": "A", "orcid": "0000-0002-1164-697X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8c283750c40b41b7959efe3f42c9ccad.json"}}, {"family": "Miron", "given": "Alexander", "initials": "A"}, {"family": "Bederman", "given": "Ilya", "initials": "I", "orcid": "0000-0002-1909-5746", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d234b19b68564c858dbc42c1f5adf9b1.json"}}, {"family": "Jankowsky", "given": "Eckhard", "initials": "E"}, {"family": "Vogel", "given": "Christine", "initials": "C", "orcid": "0000-0002-2856-3118", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/175408d95b194f04a8e8cdaf90c20933.json"}}, {"family": "Val\u00e1\u0161ek", "given": "Leo\u0161 Shivaya", "initials": "LS", "orcid": "0000-0001-8123-8667", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a73e4c57d07b45188685deb3fbe83043.json"}}, {"family": "Dinman", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-2402-9698", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/947f8aa98d194d94bdb33b6f4fce1c30.json"}}, {"family": "Zhang", "given": "Youwei", "initials": "Y", "orcid": "0000-0003-0011-7922", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/926e555efbff4fbd97f028680d69a960.json"}}, {"family": "Tirosh", "given": "Boaz", "initials": "B"}, {"family": "Larsson", "given": "Ola", "initials": "O", "orcid": "0000-0003-1412-1308", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3f81c6cbbe564d38bc78d1af5153d804.json"}}, {"family": "Topisirovic", "given": "Ivan", "initials": "I", "orcid": "0000-0002-5510-9762", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1bca1813f34c4864940ac6593044a9cc.json"}}, {"family": "Hatzoglou", "given": "Maria", "initials": "M", "orcid": "0000-0003-2037-1231", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3fbc5330f8c84c548a8472bb81cf77f3.json"}}], "type": "journal article", "published": "2025-05-00", "journal": {"title": "Nature", "issn": "1476-4687", "volume": "641", "issue": "8065", "pages": "1319-1328", "issn-l": "0028-0836"}, "abstract": "An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-\u03b1 (eIF2\u03b1, encoded by EIF2S1; eIF2\u03b1-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the 'canonical' integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2\u03b1-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2\u03b1-p induction activates the eIF4E-ATF4-PCK2 axis to maintain energy homeostasis.", "doi": "10.1038/s41586-025-08794-6", "pmid": "40140574", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12119373"}, {"db": "pii", "key": "10.1038/s41586-025-08794-6"}], "notes": [], "created": "2026-08-20T08:59:09.414Z", "modified": "2026-08-20T08:59:10.076Z"}, {"entity": "publication", "iuid": "0562f7ae9ae74ce9be218b4602dcd4c7", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/0562f7ae9ae74ce9be218b4602dcd4c7.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/0562f7ae9ae74ce9be218b4602dcd4c7"}}, "title": "The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.", "authors": [{"family": "Ghaddar", "given": "Nour", "initials": "N"}, {"family": "Wang", "given": "Shuo", "initials": "S"}, {"family": "Woodvine", "given": "Bethany", "initials": "B", "orcid": "0000-0001-8359-6476", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5b06f2ec71304b0196962103c15aefe9.json"}}, {"family": "Krishnamoorthy", "given": "Jothilatha", "initials": "J"}, {"family": "van Hoef", "given": "Vincent", "initials": "V"}, {"family": "Darini", "given": "Cedric", "initials": "C"}, {"family": "Kazimierczak", "given": "Urszula", "initials": "U"}, {"family": "Ah-Son", "given": "Nicolas", "initials": "N"}, {"family": "Popper", "given": "Helmuth", "initials": "H", "orcid": "0000-0003-4970-1265", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5c125771dd9d40b28c0ec1108a2efdb8.json"}}, {"family": "Johnson", "given": "Myriam", "initials": "M"}, {"family": "Officer", "given": "Leah", "initials": "L", "orcid": "0000-0002-3690-2386", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9244a991003b48c4a624ff9fc105c50c.json"}}, {"family": "Teod\u00f3sio", "given": "Ana", "initials": "A", "orcid": "0000-0002-1386-6730", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f87a35d99867490aaf8e1120130837a8.json"}}, {"family": "Broggini", "given": "Massimo", "initials": "M", "orcid": "0000-0002-8138-9358", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b1e8ef5869dd4419a5c540a3071e7217.json"}}, {"family": "Mann", "given": "Koren K", "initials": "KK"}, {"family": "Hatzoglou", "given": "Maria", "initials": "M", "orcid": "0000-0003-2037-1231", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3fbc5330f8c84c548a8472bb81cf77f3.json"}}, {"family": "Topisirovic", "given": "Ivan", "initials": "I", "orcid": "0000-0002-5510-9762", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1bca1813f34c4864940ac6593044a9cc.json"}}, {"family": "Larsson", "given": "Ola", "initials": "O", "orcid": "0000-0003-1412-1308", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3f81c6cbbe564d38bc78d1af5153d804.json"}}, {"family": "Le Quesne", "given": "John", "initials": "J", "orcid": "0000-0003-3552-7446", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a6bbfa845cda4379b505dbb0091edcf6.json"}}, {"family": "Koromilas", "given": "Antonis E", "initials": "AE", "orcid": "0000-0003-1972-0799", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7825afc7ac8942819083ce7c570b5508.json"}}], "type": "journal article", "published": "2021-07-30", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "12", "issue": "1", "pages": "4651", "issn-l": "2041-1723"}, "abstract": "The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2\u03b1), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2\u03b1 causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.", "doi": "10.1038/s41467-021-24661-0", "pmid": "34330898", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8324901"}, {"db": "pii", "key": "10.1038/s41467-021-24661-0"}], "notes": [], "created": "2026-08-20T08:51:39.836Z", "modified": "2026-08-20T08:51:40.199Z"}, {"entity": "publication", "iuid": "4288addfa25a47f3884be39dc34c3e89", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/4288addfa25a47f3884be39dc34c3e89.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/4288addfa25a47f3884be39dc34c3e89"}}, "title": "Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR.", "authors": [{"family": "Kaspar", "given": "Sophie", "initials": "S", "orcid": "0000-0002-0844-6432", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0cdeeebe478446cd86b3ae0be238ac03.json"}}, {"family": "Oertlin", "given": "Christian", "initials": "C"}, {"family": "Szczepanowska", "given": "Karolina", "initials": "K", "orcid": "0000-0003-4689-2350", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4526c9fd1045408d99d9f081e4331d0d.json"}}, {"family": "Kukat", "given": "Alexandra", "initials": "A", "orcid": "0000-0002-8610-0189", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/99feea57ad6c43c5b243857e88977bc6.json"}}, {"family": "Senft", "given": "Katharina", "initials": "K", "orcid": "0000-0003-2294-6481", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b044634fdab9416eae21512d1d57a822.json"}}, {"family": "Lucas", "given": "Christina", "initials": "C", "orcid": "0000-0002-6575-3877", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b3ace6f7382f4d27bce2152f8a114ed9.json"}}, {"family": "Brodesser", "given": "Susanne", "initials": "S", "orcid": "0000-0001-5631-0663", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9bb2fb66786b410d8e61f0cda2c435e5.json"}}, {"family": "Hatzoglou", "given": "Maria", "initials": "M", "orcid": "0000-0003-2037-1231", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3fbc5330f8c84c548a8472bb81cf77f3.json"}}, {"family": "Larsson", "given": "Ola", "initials": "O", "orcid": "0000-0003-1412-1308", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3f81c6cbbe564d38bc78d1af5153d804.json"}}, {"family": "Topisirovic", "given": "Ivan", "initials": "I", "orcid": "0000-0002-5510-9762", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1bca1813f34c4864940ac6593044a9cc.json"}}, {"family": "Trifunovic", "given": "Aleksandra", "initials": "A", "orcid": "0000-0002-5472-3517", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1bec355885e34065983da151480f5cfe.json"}}], "type": "journal article", "published": "2021-05-00", "journal": {"title": "Sci Adv", "issn": "2375-2548", "volume": "7", "issue": "22", "issn-l": "2375-2548"}, "abstract": "In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress response: CHOP, C/EBP\u03b2, and ATF4. We show that CHOP acts as a rheostat that attenuates prolonged ISR, prevents unfavorable metabolic alterations, and postpones the onset of mitochondrial cardiomyopathy. Upon mitochondrial dysfunction, CHOP interaction with C/EBP\u03b2 is needed to adjust ATF4 levels, thus preventing overactivation of the ATF4-regulated transcriptional program. Failure of this interaction switches ISR from an acute to a chronic state, leading to early respiratory chain deficiency, energy crisis, and premature death. Therefore, contrary to its previously proposed role as a transcriptional activator of mitochondrial unfolded protein response, our results highlight a role of CHOP in the fine-tuning of mitochondrial ISR in mammals.", "doi": "10.1126/sciadv.abf0971", "pmid": "34039602", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8153728"}, {"db": "pii", "key": "7/22/eabf0971"}], "notes": [], "created": "2026-08-20T11:58:37.274Z", "modified": "2026-08-20T11:58:37.736Z"}]}