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). The effectiveness of mTORC1 inhibitors is limited by their lack of cytotoxic effects. Here, we report that E26 transformation specific (ETS) Variant Transcription Factor 2 (ETV2) is a critical regulator of Tsc2-deficient cell survival. Nuclear localization of ETV2 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), a coregulator of transcription, mRNA and protein expression. Silencing of 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 signaling axis unique to Syk-inhibition is mTORC1-independent and promotes a cytocidal response in Tsc2-deficient cells, and therefore, maybe a potential alternative therapeutic target in LAM.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Competing interests: No competing interests declared
Data Availability: All data generated or analyzed during this study are included in the manuscript and its supporting files. Expression array data will be deposited in GEO by September the 10th N/A
Ethics: Human Subjects: Yes Ethics Statement: Human subjects: Patients were enrolled in protocols at the National Institutes of Health (NIH) Clinical Center (protocol 95-H-0186; 96-H-0100), which were approved by the National Heart, Lung, and Blood Institute Institutional Review Board and, written informed consent was obtained for each individual. Clinical Trial: No Animal Subjects: Yes Ethics Statement: All animal experimental procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee at Brigham and Women’s Hospital (Permit Number 2016N000308)
Funding: This work was supported in part by National Institutes of Health (U01-HL 131022 to S. El-Chemaly and T32HL007633-35 to J. Ng) and the Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute and the Anne Levine LAM Research Fund (S. El-Chemaly)