{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:33:47Z","timestamp":1777451627937,"version":"3.51.4"},"reference-count":68,"publisher":"Life Science Alliance, LLC","issue":"5","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U01-HL 131022"],"award-info":[{"award-number":["U01-HL 131022"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32HL007633-35"],"award-info":[{"award-number":["T32HL007633-35"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute"},{"name":"Anne Levine LAM Research Fund"}],"content-domain":{"domain":["life-science-alliance.org"],"crossmark-restriction":true},"short-container-title":["Life Sci. Alliance"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>\n                    Lymphangioleiomyomatosis (LAM) is a rare progressive disease, characterized by mutations in the tuberous sclerosis complex genes (\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    ) and hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Here, we report that E26 transformation\u2013specific (ETS) variant transcription factor 2 (ETV2) is a critical regulator of\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -deficient cell survival. ETV2 nuclear localization in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -deficient cells is mTORC1-independent and is enhanced by spleen tyrosine kinase (Syk) inhibition. In the nucleus, ETV2 transcriptionally regulates poly(ADP-ribose) polymerase 1 binding protein (PARPBP) mRNA and protein expression, partially reversing the observed down-regulation of PARPBP expression induced by mTORC1 blockade during treatment with both Syk and mTORC1 inhibitors. In addition, silencing Etv2 or\n                    <jats:italic>Parpbp<\/jats:italic>\n                    in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -deficient cells induced ER stress and increased cell death in vitro and in vivo. We also found\n                    <jats:italic>ETV2<\/jats:italic>\n                    expression in human cells with loss of heterozygosity for\n                    <jats:italic>TSC2<\/jats:italic>\n                    , lending support to the translational relevance of our findings. In conclusion, we report a novel ETV2 signaling axis unique to Syk inhibition that promotes a cytocidal response in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -deficient cells and therefore maybe a potential alternative therapeutic target in LAM.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202201369","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T13:30:17Z","timestamp":1645191017000},"page":"e202201369","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["ETV2 regulates PARP-1 binding protein to induce ER stress\u2013mediated death in tuberin-deficient cells"],"prefix":"10.26508","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9493-8814","authenticated-orcid":true,"given":"Shikshya","family":"Shrestha","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Brigham and Women\u2019s 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