INT154651

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Context Info
Confidence 0.59
First Reported 2008
Last Reported 2010
Negated 0
Speculated 2
Reported most in Body
Documents 19
Total Number 28
Disease Relevance 10.48
Pain Relevance 2.01

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

plasma membrane (Nfe2l2) nucleus (Nfe2l2) DNA binding (Nfe2l2)
cytoplasm (Nfe2l2)
Anatomy Link Frequency
fibroblasts 1
embryonic death 1
Nfe2l2 (Mus musculus)
Pain Link Frequency Relevance Heat
Paracetamol 65 98.16 Very High Very High Very High
Glutamate 14 92.56 High High
cINOD 10 83.60 Quite High
Inflammation 36 75.96 Quite High
dexamethasone 2 56.48 Quite High
ischemia 1 42.88 Quite Low
Inflammatory response 15 5.00 Very Low Very Low Very Low
Analgesic 7 5.00 Very Low Very Low Very Low
adenocard 7 5.00 Very Low Very Low Very Low
cytokine 5 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Repression 3 100.00 Very High Very High Very High
Toxicity 159 99.42 Very High Very High Very High
Stress 385 99.24 Very High Very High Very High
Cancer 66 98.48 Very High Very High Very High
Targeted Disruption 90 97.90 Very High Very High Very High
Aging 15 97.68 Very High Very High Very High
Autoimmune Disease 4 96.56 Very High Very High Very High
Death 32 95.84 Very High Very High Very High
Injury 43 95.24 Very High Very High Very High
Ataxia 76 94.60 High High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
Consequently, the two proteins whose expression was most disparately affected by loss of Nrf2 were of a similar type, again emphasising the complexity of Nrf2 regulation of lipid metabolism.
Negative_regulation (loss) of Nrf2
1) Confidence 0.59 Published 2010 Journal Journal of Proteomics Section Body Doc Link PMC2891861 Disease Relevance 0 Pain Relevance 0
The demonstration that loss of Nrf2 results in such a large up-regulation of this already abundant protein may therefore have significant implication for multiple cellular functions, and this is the subject of further investigation in our laboratories.
Negative_regulation (loss) of Nrf2
2) Confidence 0.59 Published 2010 Journal Journal of Proteomics Section Body Doc Link PMC2891861 Disease Relevance 0 Pain Relevance 0
We hypothesized that acetaminophen activates Nrf2 via the formation of its reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which may disrupt the repression of Nrf2 through the modification of cysteine residues within Keap1.
Negative_regulation (repression) of Nrf2 associated with paracetamol and repression
3) Confidence 0.58 Published 2008 Journal Hepatology Section Abstract Doc Link 18785192 Disease Relevance 0.19 Pain Relevance 0.28
While RNAi depletion of Keap1 led to reduced toxicity following exposure to DNCB, depletion of Nrf2 and NF-kappaB augmented toxicity.
Negative_regulation (depletion) of Nrf2 associated with toxicity
4) Confidence 0.56 Published 2010 Journal Biochem. Pharmacol. Section Abstract Doc Link 20416283 Disease Relevance 0.47 Pain Relevance 0.11
We also employed RNAi to manipulate Keap1 (the inhibitor of Nrf2), Nrf2 itself and NF-kappaB-p65, to understand their roles in the response to drug stress.
Negative_regulation (inhibitor) of Nrf2 associated with stress
5) Confidence 0.56 Published 2010 Journal Biochem. Pharmacol. Section Abstract Doc Link 20416283 Disease Relevance 0.53 Pain Relevance 0.13
In any case, identifying agents that reduce NRF2 protein levels, especially during oxidative stress (e.g. increasing CRIF1 protein or activity levels or blocking KEAP1-NRF2 dissociation), may be useful in clinic settings to help cope with drug-resistant cancer cells.
Negative_regulation (reduce) of NRF2 associated with stress and cancer
6) Confidence 0.48 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.90 Pain Relevance 0
Thus, Keap1 knock-out mice die shortly after birth (possibly from uncontrolled expression of Nrf2 target genes), but mice defective for both Keap1 and Nrf2 are viable (possibly because Nrf2 target genes cannot be overexpressed sufficiently to cause embryonic death in the double knock-out).
Negative_regulation (defective) of Nrf2 in embryonic death associated with targeted disruption and death
7) Confidence 0.48 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.82 Pain Relevance 0
Inactivation of the nrf2 gene results in no obvious phenotypic changes (except in aging female animals, where autoimmune diseases have been observed [22]), indicating that Nrf2 is not essential for normal growth and development [23].
Negative_regulation (Inactivation) of nrf2 associated with autoimmune disease and aging
8) Confidence 0.43 Published 2010 Journal Journal of Proteomics Section Body Doc Link PMC2891861 Disease Relevance 0.59 Pain Relevance 0.04
mice clearly indicates that protection against chemical toxins that undergo bioactivation to chemically reactive species, such as electrophiles, may be severely compromised due to lack of Nrf2 under basal conditions.
Negative_regulation (lack) of Nrf2
9) Confidence 0.43 Published 2010 Journal Journal of Proteomics Section Body Doc Link PMC2891861 Disease Relevance 0.07 Pain Relevance 0
Mice lacking Nrf2 are more susceptible to carcinogenesis induced by carcinogens.
Negative_regulation (lacking) of Nrf2
10) Confidence 0.43 Published 2008 Journal Planta Med. Section Abstract Doc Link 18937168 Disease Relevance 0.74 Pain Relevance 0.35
Nrf2 activation has been proposed to occur through the modification of cysteine residues within Keap1, the cytosolic repressor of Nrf2.
Negative_regulation (repressor) of Nrf2
11) Confidence 0.42 Published 2008 Journal Hepatology Section Abstract Doc Link 18785192 Disease Relevance 0.18 Pain Relevance 0.26
By promoting the inactivation of Nrf2-keap1 complex and increased binding to no-1ARE, curcumin induces hemoxygenase activity.
Negative_regulation (inactivation) of Nrf2
12) Confidence 0.42 Published 2008 Journal Annals of Indian Academy of Neurology Section Body Doc Link PMC2781139 Disease Relevance 0.42 Pain Relevance 0.05
Interestingly, increased Nrf2 caused by Keap1 depletion was reversed by co-depletion of NF-kappaB.
Negative_regulation (reversed) of Nrf2
13) Confidence 0.41 Published 2010 Journal Biochem. Pharmacol. Section Abstract Doc Link 20416283 Disease Relevance 0.41 Pain Relevance 0.11
While RNAi depletion of Keap1 led to reduced toxicity following exposure to DNCB, depletion of Nrf2 and NF-?
Negative_regulation (depletion) of Nrf2 associated with toxicity
14) Confidence 0.35 Published 2010 Journal Biochemical Pharmacology Section Abstract Doc Link PMC2884179 Disease Relevance 0.48 Pain Relevance 0.11
To test whether endogenous CRIF1 negatively regulates endogenous NRF2 protein levels, we first reduced the negative regulation of endogenous NRF2 of CRIF1 by using CRIF1-specific siRNAs.
Negative_regulation (regulation) of NRF2
15) Confidence 0.35 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0 Pain Relevance 0
As expected, overexpression of either CRIF1 or KEAP1 reduced exogenous wild-type NRF2 protein levels in total cell lysates (Fig. 4A, 2nd panel from the top, lanes 2 and 3).
Negative_regulation (reduced) of NRF2
16) Confidence 0.35 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0 Pain Relevance 0
Because our study showed that knockdown of endogenous CRIF1 enhanced SFN-induced NRF2 total and nuclear expression (Fig. 3, C and D), we determined whether the induced nuclear NRF2 binds to an ARE-containing DNA sequence.
Negative_regulation (knockdown) of NRF2
17) Confidence 0.35 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0 Pain Relevance 0
Are CRIF1 and KEAP1 negative regulations of NRF2 completely independent of one another?
Negative_regulation (regulations) of NRF2
18) Confidence 0.35 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.15 Pain Relevance 0
However, the most important difference between CRIF1 and KEAP1 negative regulation of NRF2 may have physiological significance, i.e. the unique ability of CRIF1 (but not KEAP1) to negatively regulate NRF2 protein levels under conditions of oxidative stress.
Negative_regulation (regulation) of NRF2 associated with stress
19) Confidence 0.35 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2898415 Disease Relevance 0.21 Pain Relevance 0
In summary, our results demonstrate that knockdown of CRIF1 and KEAP1 can independently increase expression from NRF2 target gene reporter plasmids, strongly suggesting that normal levels of CRIF1 and KEAP1 can independently limit NRF2 protein levels and its ability to stimulate genomic transcription.


Negative_regulation (limit) of NRF2
20) Confidence 0.35 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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