INT319663

Context Info Confidence 0.40 First Reported 2010 Last Reported 2010 Negated 1 Speculated 0 Reported most in Body Documents 1 Total Number 11 Disease Relevance 2.83 Pain Relevance 0.17

nucleus (Nfe2l2, Keap1) cytoplasm (Nfe2l2, Keap1) endoplasmic reticulum (Keap1) plasma membrane (Nfe2l2) DNA binding (Nfe2l2)

Nfe2l2 (Mus musculus) Keap1 (Mus musculus)

Pain Link Frequency Relevance Heat Paracetamol 11 86.96

Disease Link Frequency Relevance Heat Stress 253 99.34 Chronic Disease 11 90.00 Aging 11 66.88 Cancer 66 66.48 Targeted Disruption 33 20.24 Sprains And Strains 11 5.00 Death 11 5.00

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

There are also several differences between the activity of CRIF1 and KEAP1; for example, 1) CRIF1 interacts with both the N and C termini of NRF2 protein, whereas KEAP1 interacts with only the N terminus of NRF2; and 2) KEAP1 cannot interact with ETGE point mutants of NRF2, whereas CRIF1 can.

NRF2 Neg (cannot) Binding (interact) of KEAP1

1) Confidence 0.40 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.20 Pain Relevance 0

There are also several differences between the activity of CRIF1 and KEAP1; for example, 1) CRIF1 interacts with both the N and C termini of NRF2 protein, whereas KEAP1 interacts with only the N terminus of NRF2; and 2) KEAP1 cannot interact with ETGE point mutants of NRF2, whereas CRIF1 can.

NRF2 Binding (interacts) of KEAP1

2) Confidence 0.31 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.21 Pain Relevance 0

In addition, we found that CRIF1, unlike KEAP1 (which only interacts with N-terminal region of NRF2), physically interacts with both N- and C-terminal regions of NRF2 and promotes NRF2 ubiquitination and subsequent proteasome-mediated NRF2 protein degradation.

NRF2 Binding (interacts) of KEAP1

3) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2898415 Disease Relevance 0.38 Pain Relevance 0

To test whether exogenous CRIF1 can affect NRF2 and NRF2 target gene mRNA levels when functional KEAP1-NRF2 interactions are eliminated, cells were infected with adenovirus (GFP versus GFP-CRIF1) (19) for 24 h and then treated with t-BHQ (100 ?

NRF2 Binding (interactions) of KEAP1

4) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.06 Pain Relevance 0

Two molecules of KEAP1 bind to two distinct sites in the N-terminal region of NRF2, the ETGE and DLG sites, which affect the KEAP1-NRF2 interaction and/or its physiological consequences (12–14).

NRF2 Binding (interaction) of KEAP1

5) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.45 Pain Relevance 0.09

Two molecules of KEAP1 bind to two distinct sites in the N-terminal region of NRF2, the ETGE and DLG sites, which affect the KEAP1-NRF2 interaction and/or its physiological consequences (12–14).

NRF2 Binding (interaction) of KEAP1

6) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.45 Pain Relevance 0.09

In addition, we found that CRIF1, unlike KEAP1 (which only interacts with N-terminal region of NRF2), physically interacts with both N- and C-terminal regions of NRF2 and promotes NRF2 ubiquitination and subsequent proteasome-mediated NRF2 protein degradation.

NRF2 Binding (interacts) of KEAP1

7) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2898415 Disease Relevance 0.38 Pain Relevance 0

There are also several differences between the activity of CRIF1 and KEAP1; for example, 1) CRIF1 interacts with both the N and C termini of NRF2 protein, whereas KEAP1 interacts with only the N terminus of NRF2; and 2) KEAP1 cannot interact with ETGE point mutants of NRF2, whereas CRIF1 can.

NRF2 Binding (interacts) of KEAP1

8) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.20 Pain Relevance 0

Previous studies and our current studies found that KEAP1 interacts only with the most N-terminal region of NRF2 (data not shown) (29).

NRF2 Binding (interacts) of KEAP1

9) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0 Pain Relevance 0

Previously, it has been shown that NRF2 protein levels increase after oxidative stress because its negative regulator, KEAP1, loses its ability to bind NRF2 and cause its proteasome-mediated degradation during oxidative stress.

NRF2 Binding (bind) of KEAP1 associated with stress

10) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2898415 Disease Relevance 0.44 Pain Relevance 0

To test whether exogenous CRIF1 can affect NRF2 and NRF2 target gene mRNA levels when functional KEAP1-NRF2 interactions are eliminated, cells were infected with adenovirus (GFP versus GFP-CRIF1) (19) for 24 h and then treated with t-BHQ (100 ?

NRF2 Binding (interactions) of KEAP1

11) Confidence 0.30 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.06 Pain Relevance 0

General Comments

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