Related Experiment Video

Updated: Oct 3, 2025

Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
10:50

Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons

Published on: April 24, 2021

1.1K

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

Shikshya Shrestha1, Anthony Lamattina2, Gustavo Pacheco-Rodriguez3

  • 1Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA sshrestha4@partners.org.

Life Science Alliance
|February 19, 2022
PubMed

Insights

A novel ETV2 signaling pathway promotes cell death in Tuberous Sclerosis Complex 2 (TSC2)-deficient cells, offering a potential new therapeutic target for Lymphangioleiomyomatosis (LAM). This pathway is independent of mTORC1 and enhanced by Syk inhibition.

Area of Science:

  • Cell Biology
  • Oncology
  • Genetics

Background:

  • Lymphangioleiomyomatosis (LAM) is a rare, progressive disease linked to mutations in TSC1 or TSC2 genes, leading to mTORC1 hyperactivation.
  • Understanding the molecular mechanisms governing TSC2-deficient cell survival is crucial for developing effective LAM therapies.

Purpose of the Study:

  • To investigate the role of E26 transformation-specific (ETS) variant transcription factor 2 (ETV2) in TSC2-deficient cell survival.
  • To explore the interplay between ETV2, spleen tyrosine kinase (Syk) inhibition, and mechanistic target of rapamycin complex 1 (mTORC1) signaling in LAM pathogenesis.

Main Methods:

  • Analysis of ETV2 nuclear localization in TSC2-deficient cells under varying conditions (Syk inhibition, mTORC1 blockade).
  • Assessment of ETV2's transcriptional regulation of poly(ADP-ribose) polymerase 1 binding protein (PARPBP).
  • In vitro and in vivo studies involving gene silencing of Etv2 and Parpbp in TSC2-deficient cells.

Main Results:

  • ETV2 nuclear localization in TSC2-deficient cells is independent of mTORC1 and is enhanced by Syk inhibition.
  • ETV2 regulates PARPBP expression, partially reversing mTORC1 blockade-induced downregulation.
  • Silencing Etv2 or Parpbp in TSC2-deficient cells leads to ER stress and increased cell death, with ETV2 expression found in human TSC2-deficient cells.

Conclusions:

  • A novel ETV2 signaling axis, unique to Syk inhibition, promotes a cytocidal response in TSC2-deficient cells.
  • This ETV2-PARPBP pathway represents a potential alternative therapeutic target for Lymphangioleiomyomatosis (LAM).

More Related Videos

Author Spotlight: Exploring the Role of Unfolded Protein Response in HIV-1 Replication and Infectivity10:12

Author Spotlight: Exploring the Role of Unfolded Protein Response in HIV-1 Replication and Infectivity

Published on: June 14, 2024

2.2K
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.3K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.1K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.6K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
5.2K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.7K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.0K