INT101820

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Context Info
Confidence 0.58
First Reported 2002
Last Reported 2010
Negated 0
Speculated 1
Reported most in Abstract
Documents 20
Total Number 21
Disease Relevance 18.79
Pain Relevance 0.19

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

endoplasmic reticulum (KEAP1) nucleolus (KEAP1) nucleus (KEAP1)
cytoplasm (KEAP1)
Anatomy Link Frequency
lung 5
A549 2
H460 1
KEAP1 (Homo sapiens)
Pain Link Frequency Relevance Heat
cINOD 3 57.04 Quite High
Inflammation 37 51.36 Quite High
Glutamate 19 5.00 Very Low Very Low Very Low
palliative 18 5.00 Very Low Very Low Very Low
Paracetamol 1 5.00 Very Low Very Low Very Low
Osteoarthritis 1 5.00 Very Low Very Low Very Low
Pain 1 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Non-small-cell Lung Cancer 432 99.92 Very High Very High Very High
Lung Cancer 974 99.84 Very High Very High Very High
Cancer 1880 99.68 Very High Very High Very High
Adenocarcinoma 128 97.48 Very High Very High Very High
Malignant Neoplastic Disease 72 97.28 Very High Very High Very High
Stress 153 89.36 High High
Carcinoma 18 88.24 High High
Repression 19 88.08 High High
Carcinoma In Situ 18 86.44 High High
Cleidocranial Dysplasia 18 85.52 High High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
In corroboration with the above findings that suggest loss of functional KEAP1 in lung cancers, immunohistochemical staining of NRF2 in lung adenocarcinoma tissues showed increased staining in tumor tissue compared to paired normal tissue.
Negative_regulation (loss) of KEAP1 in lung associated with adenocarcinoma, lung cancer and cancer
1) Confidence 0.58 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.06 Pain Relevance 0
Also, KEAP1 downregulation by promoter methylation cannot be ruled out because the KEAP1 promoter contains CpG-rich regions.
Negative_regulation (downregulation) of KEAP1
2) Confidence 0.58 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.94 Pain Relevance 0
The identification of KEAP1 mutations in a subset of NSCLC samples and the association between loss of functional KEAP1 and increased NRF2 activity extends the emerging paradigm whereby increased expression of antioxidants, detoxification enzymes, and drug transporters favors malignant progression and renders tumors resistant to chemotherapy.
Negative_regulation (loss) of KEAP1 associated with malignant neoplastic disease, cancer and non-small-cell lung cancer
3) Confidence 0.58 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.12 Pain Relevance 0
Importantly, expression of KEAP1 mRNA was downregulated in three cancer cell lines—A549, H1435, and H838 (Figure 4D)—and KEAP1 protein was downregulated in all four cancer cell lines in comparison with expression in non-malignant cells (Figures 4A–4C and S4).


Negative_regulation (downregulated) of KEAP1 protein in A549 associated with malignant neoplastic disease and cancer
4) Confidence 0.58 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.13 Pain Relevance 0
Here, we report—to our knowledge for the first time—biallelic inactivation of KEAP1 in NSCLC, which we believe would result in constitutive activation of NRF2.
Negative_regulation (inactivation) of KEAP1 associated with non-small-cell lung cancer
5) Confidence 0.58 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.09 Pain Relevance 0
All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity.
Negative_regulation (abolish) of KEAP1
6) Confidence 0.58 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 0.97 Pain Relevance 0
Five of the six PTs harboring KEAP1 mutations showed LOH of KEAP1; thus, as defined by the Knudson two-hit model, there was biallelic inactivation of KEAP1 in these tumors [32].
Negative_regulation (inactivation) of KEAP1 associated with cancer
7) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.34 Pain Relevance 0
These results indicate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC and suggest that the loss of KEAP1 activity is one way that lung tumors can increase their NRF2 activity and develop resistance to chemotherapeutic drugs.
Negative_regulation (loss) of KEAP1 in lung associated with lung cancer and non-small-cell lung cancer
8) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 1.22 Pain Relevance 0
Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.



Negative_regulation (Loss) of KEAP1 associated with cancer
9) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 1.19 Pain Relevance 0
More lung cancer samples need to be examined to confirm this result, and similar studies need to be done in other cancers to see whether loss of KEAP1 activity is a common mechanism by which tumors become resistant to chemotherapy.
Spec (whether) Negative_regulation (loss) of KEAP1 in lung associated with lung cancer and cancer
10) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 1.09 Pain Relevance 0
We detected point mutations leading to non-conservative amino acid substitutions and nonsense mutations in 50% (6/12) of the cell lines sequenced (Table 1), and all the mutations altered highly conserved amino acid residues located in the Kelch or IVR domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity.
Negative_regulation (abolish) of KEAP1
11) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.00 Pain Relevance 0.03
Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.


Negative_regulation (Decreased) of KEAP1 associated with cancer
12) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 1.00 Pain Relevance 0
Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event.
Negative_regulation (inactivation) of KEAP1 in lung associated with lung cancer
13) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 0.80 Pain Relevance 0
This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC.
Negative_regulation (inactivation) of KEAP1 associated with non-small-cell lung cancer
14) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 1.12 Pain Relevance 0
These results indicate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC and suggest that the loss of KEAP1 activity is one way that lung tumors can increase their NRF2 activity and develop resistance to chemotherapeutic drugs.
Negative_regulation (inactivation) of KEAP1 in lung associated with lung cancer and non-small-cell lung cancer
15) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 1.27 Pain Relevance 0
The microsatellite database at the Sanger Institute revealed that H460, A549, and H838 cell lines had allelic loss at 19p13.2, which confirms that the wild-type KEAP1 allele was lost by LOH and that the retained allele was inactivated by somatic mutations.
Negative_regulation (lost) of KEAP1 in H460
16) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.63 Pain Relevance 0
This finding suggests that loss of both functional KEAP1 alleles is essential for constitutive activation of NRF2-mediated gene expression.
Negative_regulation (loss) of KEAP1
17) Confidence 0.43 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.15 Pain Relevance 0
Ectopic expression of SQSTM1 led to a decrease in the basal protein level of Keap1 in a panel of cells.
Negative_regulation (decrease) of Keap1
18) Confidence 0.39 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2878012 Disease Relevance 0 Pain Relevance 0
Immunoprecipitation studies showed that indomethacin treatment also inhibited Nrf2 tethering to KIAA0132 (the human homolog of Keap1 accession #D50922), which is believed to be a negative regulator of Nrf2.
Negative_regulation (inhibited) of KIAA0132
19) Confidence 0.35 Published 2002 Journal Free Radic. Biol. Med. Section Abstract Doc Link 11909699 Disease Relevance 0.05 Pain Relevance 0.17
Upon induction, Nrf2 is stabilized because of impaired Keap1-E3 ubiquitin ligase activity, which results in activation of the Nrf2 signaling pathway (Cullinan et al. 2004; Furukawa and Xiong 2005; Kobayashi et al. 2004; Sun et al. 2007; Zhang et al. 2004b).
Negative_regulation (impaired) of Keap1
20) Confidence 0.28 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0 Pain Relevance 0

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