Related Experiment Video

Updated: Jun 5, 2026

Measurements of Physiological Stress Responses in C. Elegans
10:36

Measurements of Physiological Stress Responses in C. Elegans

Published on: May 21, 2020

Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution

Keiko Taguchi1, Hozumi Motohashi, Masayuki Yamamoto

  • 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|January 22, 2011
PubMed

Insights

The Keap1–Nrf2 pathway protects cells from damage. Mutations in Keap1 and Nrf2 genes lead to cancer cell proliferation, suggesting Nrf2 inhibitors could be effective cancer therapies.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell protection
  • Cancer research

Background:

  • The Keap1–Nrf2 pathway is crucial for cellular defense against oxidative and xenobiotic stress.
  • Under normal conditions, Nrf2 is ubiquitinated by the Cul3–Keap1 E3 ligase complex and degraded.
  • Stress triggers Keap1 modification, stabilizing Nrf2 and inducing protective genes.

Purpose of the Study:

  • To elucidate the structural basis of Keap1–Nrf2 interaction and its role in ubiquitination.
  • To investigate the impact of KEAP1 and NRF2 mutations in human cancers.
  • To explore the therapeutic potential of targeting the Keap1–Nrf2 pathway in cancer.

Main Methods:

  • Biochemical analyses of the Keap1–Nrf2 complex.
  • Structural studies of the Keap1–Nrf2 interaction.
  • Analysis of genetic mutations in KEAP1 and NRF2 in cancer patient data.

Main Results:

  • The Keap1 homodimer binds Nrf2 via two sites on Nrf2's Neh2 domain, critical for ubiquitination.
  • Missense mutations in KEAP1 and NRF2 are common in human cancers.
  • These mutations disrupt Keap1–Nrf2 complex function, leading to constitutive Nrf2 activation.

Conclusions:

  • The Keap1–Nrf2 interaction is essential for regulating Nrf2 stability and cellular defense.
  • Aberrant Nrf2 activation due to genetic mutations promotes cancer cell survival and proliferation.
  • Targeting Nrf2 inhibition presents a promising strategy for cancer treatment.

Related Concept Videos

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...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

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 heterodimer of NF-κB...
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...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

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...
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...