TY - JOUR T1 - ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201369 VL - 5 IS - 5 SP - e202201369 AU - Shikshya Shrestha AU - Anthony Lamattina AU - Gustavo Pacheco-Rodriguez AU - Julie Ng AU - Xiaoli Liu AU - Abhijeet Sonawane AU - Jewel Imani AU - Weiliang Qiu AU - Kosmas Kosmas AU - Pierce Louis AU - Anne Hentschel AU - Wendy K Steagall AU - Rieko Onishi AU - Helen Christou AU - Elizabeth P Henske AU - Kimberly Glass AU - Mark A Perrella AU - Joel Moss AU - Kelan Tantisira AU - Souheil El-Chemaly Y1 - 2022/05/01 UR - https://www.life-science-alliance.org/content/5/5/e202201369.abstract N2 - 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. ER -