Related Experiment Video

Updated: Jan 4, 2026

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
08:47

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Published on: May 1, 2020

3.3K

A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal

Stefanie Schmidt1,2, David Gay3, Friedrich Wilhelm Uthe1,2

  • 1Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany.

Nature Cell Biology
|November 6, 2019
PubMed

Insights

Colorectal tumours rely on eIF2B5 for survival. Inhibiting GCN2, which targets a MYC-eIF2α feedback loop, shows therapeutic promise for these cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Tumour growth and survival are linked to altered protein synthesis rates.
  • Mechanisms controlling mRNA translation are potential therapeutic targets.
  • Loss of Adenomatous Polyposis Coli (APC) is common in colorectal tumours.

Purpose of the Study:

  • To investigate the role of the translation initiation factor eIF2B5 in APC-deficient colorectal tumours.
  • To explore the therapeutic potential of targeting the MYC-eIF2α feedback loop.

Main Methods:

  • Depletion of eIF2B5 in APC-deficient models.
  • Analysis of MYC translation and integrated stress response.
  • Pharmacological inhibition of GCN2 kinase.
  • In vivo and organoid studies using murine and patient-derived models.

Main Results:

  • Loss of APC enhances dependence on eIF2B5.
  • eIF2B5 depletion induces stress response and MYC translation, leading to apoptosis.
  • eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient settings.
  • A negative feedback loop involving MYC, eIF2α phosphorylation, GCN2, and PKR was identified.

Conclusions:

  • eIF2B5 is crucial for preventing apoptosis in APC-deficient colorectal tumours.
  • Pharmacological inhibition of GCN2 mimics eIF2B5 depletion effects.
  • The MYC-eIF2α feedback loop represents a targetable vulnerability in colorectal cancer.

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

585
Assessment of Selective mRNA Translation in Mammalian Cells by Polysome Profiling10:00

Assessment of Selective mRNA Translation in Mammalian Cells by Polysome Profiling

Published on: October 28, 2014

28.8K

Related Concept Videos

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...
5.0K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
38.2K
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...
4.6K
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...
8.1K
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
11.6K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
5.3K