{"doi":"10.26508/lsa.202201369","title":"ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells","abstract":"Lymphangioleiomyomatosis (LAM) is a rare progressive disease, characterized by mutations in the tuberous sclerosis complex genes ( TSC1 or TSC2 ) and hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Here, we report that E26 transformation–specific (ETS) variant transcription factor 2 (ETV2) is a critical regulator of Tsc2 -deficient cell survival. ETV2 nuclear localization in Tsc2 -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 Parpbp in Tsc2 -deficient cells induced ER stress and increased cell death in vitro and in vivo. We also found ETV2 expression in human cells with loss of heterozygosity for TSC2 , 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 Tsc2 -deficient cells and therefore maybe a potential alternative therapeutic target in LAM.","journal":"Life Science Alliance","year":2022,"id":265685,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320047,"name":"Anthony M. Lamattina","orcid":"0009-0005-7947-1511","position":1,"is_corresponding":false},{"id":387864,"name":"Gustavo Pacheco–Rodriguez","orcid":"0000-0002-2793-7122","position":2,"is_corresponding":false},{"id":678984,"name":"Julie Ng","orcid":"0000-0003-0490-208X","position":3,"is_corresponding":false},{"id":368957,"name":"Xiaoli Liu","orcid":"0000-0003-2904-4413","position":4,"is_corresponding":false},{"id":226261,"name":"Abhijeet R. Sonawane","orcid":"0000-0002-1166-6479","position":5,"is_corresponding":false},{"id":451383,"name":"Jewel Imani","orcid":"0009-0009-4302-0443","position":6,"is_corresponding":false},{"id":572466,"name":"Weiliang Qiu","orcid":"0000-0002-9155-6957","position":7,"is_corresponding":false},{"id":731658,"name":"Kosmas Kosmas","orcid":"0000-0002-9712-2615","position":8,"is_corresponding":false},{"id":451384,"name":"Pierce H. Louis","orcid":"0000-0002-6521-7812","position":9,"is_corresponding":false},{"id":741782,"name":"Anne Hentschel","orcid":null,"position":10,"is_corresponding":false},{"id":831940,"name":"Wendy K. Steagall","orcid":"0000-0001-6593-8321","position":11,"is_corresponding":false},{"id":832491,"name":"Rieko Onishi","orcid":null,"position":12,"is_corresponding":false},{"id":277715,"name":"Helen Christou","orcid":"0000-0002-3104-4570","position":13,"is_corresponding":false},{"id":247628,"name":"Elizabeth P. Henske","orcid":"0000-0001-7978-6699","position":14,"is_corresponding":false},{"id":36157,"name":"Kimberly Glass","orcid":"0000-0003-4394-5779","position":15,"is_corresponding":false},{"id":368956,"name":"Mark A. Perrella","orcid":"0000-0002-7219-7688","position":16,"is_corresponding":false},{"id":241249,"name":"Joel Moss","orcid":"0000-0003-1788-1927","position":17,"is_corresponding":false},{"id":320638,"name":"Kelan G. Tantisira","orcid":"0000-0003-2950-3384","position":18,"is_corresponding":false},{"id":320051,"name":"Souheil El‐Chemaly","orcid":"0000-0003-2929-5589","position":19,"is_corresponding":false},{"id":53116,"name":"Shikshya Shrestha","orcid":"0000-0001-9493-8814","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T00:26:49.862989Z","pmid":"35181635","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}