Related Experiment Video
Updated: Oct 14, 2025
10:50
Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
Published on: April 24, 2021
1.1K
Nrf2/Keap1/ARE signaling: Towards specific regulation
Alexey V Ulasov1, Andrey A Rosenkranz2, Georgii P Georgiev1
1Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia.
Life Sciences
|November 4, 2021
Summary
The Nrf2-Keap1 pathway regulates cellular defense against oxidative stress. Inhibiting Keap1 can activate Nrf2 for treating diseases like COVID-19, with non-electrophilic inhibitors offering greater specificity.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- The Nrf2 transcription factor controls genes vital for combating oxidative stress, a key factor in diseases like neurodegeneration, cardiovascular conditions, diabetes, and viral infections.
- Nrf2 activity is primarily regulated by its interaction with the Keap1 protein, which targets Nrf2 for degradation under normal conditions but releases it during oxidative stress to activate protective genes.
Purpose of the Study:
- To explore the therapeutic potential of activating the Nrf2 system for treating oxidative stress-related diseases, including viral infections like COVID-19.
- To evaluate strategies for inactivating the Keap1 protein's regulatory function on Nrf2.
Main Methods:
- Investigating two primary approaches to Nrf2 system activation: modification of Keap1 via electrophilic agents and direct interruption of Nrf2:Keap1 protein-protein interactions (PPI).
- Comparing the specificity and potential side effects of electrophilic inducers versus non-electrophilic inhibitors of Nrf2:Keap1 PPI.
Main Results:
- Electrophilic agents targeting Keap1 may cause non-specific interactions with other cellular proteins, potentially leading to adverse effects.
- Non-electrophilic inhibitors of Nrf2:Keap1 PPI demonstrate higher specificity, suggesting a broader therapeutic window.
Conclusions:
- Activating the Nrf2 pathway is a promising strategy for treating various pathologies linked to oxidative stress.
- Non-electrophilic inhibitors of Nrf2:Keap1 PPI represent a potentially safer and more effective therapeutic approach compared to electrophilic inducers.
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
7.9K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
7.9K
01:31Regulation of the Unfolded Protein Response
2.7K
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...
2.7K
01:45Regulation of Nuclear Protein Sorting
2.6K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.6K
01:19Interactions Between Signaling Pathways
6.6K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.6K
01:07MAPK Signaling Cascades
6.5K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
6.5K
01:31Transducer Mechanism: Nuclear Receptors
1.9K
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
1.9K