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Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and
1Department of Pharmacology, Baylor College of Medicine, Texas 77030-3498, USA.
Abstract:
Antioxidant response element (ARE)-mediated expression and coordinated induction of genes encoding detoxifying enzymes is one mechanism of critical importance to cellular protection against oxidative stress. In the present report, we demonstrate that nuclear transcription factors Nrf2 and Nrf1 associate with Jun (c-Jun, Jun-B and Jun-D) proteins to upregulate ARE-mediated expression and coordinated induction of detoxifying enzymes in response to antioxidants and xenobiotics. Nrf-Jun association/heterodimerization and binding to the ARE required unknown cytosolic factor(s). Nrf2 containing one mutated leucine in its leucine zipper region was more efficient in upregulation of ARE-mediated gene expression, as compared to Nrf1 with two mutated leucines.
Insights
Nuclear transcription factors Nrf2 and Nrf1 bind with Jun proteins to boost detoxifying enzyme production, crucial for cellular defense against oxidative stress. This interaction enhances cellular protection mechanisms.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Cellular protection against oxidative stress is vital.
- Antioxidant Response Element (ARE)-mediated gene expression is a key protective mechanism.
- Detoxifying enzymes play a critical role in cellular defense.
Purpose of the Study:
- To investigate the role of nuclear transcription factors Nrf1 and Nrf2 in ARE-mediated gene expression.
- To determine the association of Nrf1 and Nrf2 with Jun proteins.
- To elucidate the mechanism of coordinated induction of detoxifying enzymes.
Main Methods:
- Demonstration of Nrf1 and Nrf2 association with Jun proteins (c-Jun, Jun-B, Jun-D).
- Analysis of ARE-mediated gene expression in response to antioxidants and xenobiotics.
- Investigation of the role of cytosolic factors in Nrf-Jun complex formation and ARE binding.
- Mutational analysis of leucine zipper regions in Nrf1 and Nrf2.
Main Results:
- Nuclear transcription factors Nrf1 and Nrf2 associate with Jun proteins.
- This association upregulates ARE-mediated expression and coordinated induction of detoxifying enzymes.
- Nrf-Jun association and ARE binding require unknown cytosolic factors.
- Mutant Nrf2 with one mutated leucine was more efficient than Nrf1 with two mutated leucines in upregulating ARE-mediated gene expression.
Conclusions:
- Nrf1 and Nrf2, in association with Jun proteins, are crucial for ARE-mediated gene expression.
- This complex regulates the induction of detoxifying enzymes, enhancing cellular protection.
- Cytosolic factors are necessary for the formation and function of the Nrf-Jun complex at the ARE.