ETV2 regulates PARP-1 binding protein to induce ER stress-mediated death in tuberin-deficient cells
| Autor: | Shikshya Shrestha, Anthony Lamattina, Gustavo Pacheco-Rodriguez, Julie Ng, Xiaoli Liu, Abhijeet Sonawane, Jewel Imani, Weiliang Qiu, Kosmas Kosmas, Pierce Louis, Anne Hentschel, Wendy K Steagall, Rieko Onishi, Helen Christou, Elizabeth P Henske, Kimberly Glass, Mark A Perrella, Joel Moss, Kelan Tantisira, Souheil El-Chemaly |
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| Rok vydání: | 2022 |
| Předmět: |
DNA-Binding Proteins
Ecology Health Toxicology and Mutagenesis Tumor Suppressor Proteins Tuberous Sclerosis Complex 2 Protein Humans Plant Science Lymphangioleiomyomatosis Mechanistic Target of Rapamycin Complex 1 Poly(ADP-ribose) Polymerase Inhibitors Endoplasmic Reticulum Stress Biochemistry Genetics and Molecular Biology (miscellaneous) Transcription Factors |
| Zdroj: | Life science alliance. 5(5) |
| ISSN: | 2575-1077 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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