ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling

Kim, Ju Young; Lee, Dong Hun; Kim, Joo Kyung; Choi, Hong Seo; Dwivedi, Bhakti; Rupji, Manali; Kowalski, Jeanne; Green, Stefan J.; Song, Heesang; Park, Won-Jong; Chang, Ji Young; Kim, Tae Min; Park, Changwon

doi:10.1186/s13287-019-1466-8

Cited by 15 publications

(22 citation statements)

References 42 publications

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“…A known target of ETV2, acting as a transcription factor, are genes involved in the regulatory networks for hematopoietic and endothelial lineages, including Flk1 (Kim et al, 2019). We used PANDA network analysis and identified multiple genes that could be potential transcriptional targets of ETV2 following Syk inhibition in Tsc2-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells

et al. 2022

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“…Known target genes of ETV2, acting as a transcription factor, are genes involved in the regulatory networks for hematopoietic and endothelial lineages, including Flk1 (Kim et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

ETV2 regulates PARP-1 binding protein to induce ER stress-mediated cell death in tuberin-deficient cells

Shrestha

Lamattina

Pacheco–Rodriguez

et al. 2021

Preprint

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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.

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“…However, the related molecular mechanism of Tai Chi exercise remains unclear. Mitogen-activated protein kinase (MAPK) signaling plays a critical role in the pathogenesis of CHD [31,32] and can be activated by miR-126 [33,34]. miR-126 is an independent risk factor of CHD and affects many important gene expression [35,36].…”

Section: Introductionmentioning

confidence: 99%

Tai Chi Improves Coronary Heart Disease Risk by Inactivating MAPK/ERK Pathway through Serum miR‐126

Zhang

Wang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Background. Tai Chi is effective in preventing heart disease (CHD) risk, but the molecular mechanism remains unclear. Mitogen-activated protein kinase (MAPK) signaling plays a critical role in the pathogenesis of CHD and can be activated by miR-126. Tai Chi may exert its protective function through the miR-126-modulated MAPK pathway. Methods. The CHD patients after PCI were randomized into the CG group (CG) (n = 19, normal care) and Tai Chi group (TG) (Tai Chi intervention, n = 17). Epicardial adipose tissue volume (EATV) (one main adverse cardiovascular event of CHD), HR (heart rate), QoL (quality of life) scores, and balance performance were measured in the two groups. The body fat content, abdominal subcutaneous fat, and visceral fat were measured to reflect the improvement of adipose tissue dysfunction. The levels of miR-126 and MAPK-associated molecules were measured in peripheral blood leukocytes. Meanwhile, the effects of miR-126 silence and mimic on MAPK-associated molecules were also explored in cardiac cell H9C2. Results. After the 3-month intervention, Tai Chi reduced EATV and HR and increased QoL scores and balance performance, respectively (P<0.05). The fat percentage, body fat mass, and BMI were also significantly reduced after Tai Chi intervention (P<0.05). The levels of miR-126, MAPK, JNK, and ERK in the TG group were lower than those in the CG group (P<0.05). The miR-126 levels had a strong relationship with the values of EATV, HR, and QoL scores (P<0.05). miR-126 silence or mimic inactivated or activated MAPK-associated molecules in the cardiac cell lines. Conclusions. Tai Chi improved CHD risk by inactivating the MAPK/ERK pathway via serum miR-126.

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ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling

Cited by 15 publications

References 42 publications

ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells

ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells

ETV2 regulates PARP-1 binding protein to induce ER stress-mediated cell death in tuberin-deficient cells

Tai Chi Improves Coronary Heart Disease Risk by Inactivating MAPK/ERK Pathway through Serum miR‐126

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