INT101817

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Context Info
Confidence 0.59
First Reported 2002
Last Reported 2010
Negated 1
Speculated 0
Reported most in Body
Documents 13
Total Number 19
Disease Relevance 6.71
Pain Relevance 0.17

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

cytosol (NFE2L2) plasma membrane (NFE2L2) nucleus (NFE2L2)
DNA binding (NFE2L2) cytoplasm (NFE2L2)
Anatomy Link Frequency
Hepa-1c1c7 1
lung 1
MDA-MB-231 1
NFE2L2 (Homo sapiens)
Pain Link Frequency Relevance Heat
cINOD 3 65.12 Quite High
Inflammation 16 36.64 Quite Low
Glutamate 12 24.68 Low Low
Osteoarthritis 7 5.00 Very Low Very Low Very Low
Pain 7 5.00 Very Low Very Low Very Low
Paracetamol 6 5.00 Very Low Very Low Very Low
palliative 5 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Stress 101 99.64 Very High Very High Very High
Cancer 568 98.98 Very High Very High Very High
Death 118 98.80 Very High Very High Very High
Toxicity 97 97.16 Very High Very High Very High
Targeted Disruption 12 96.76 Very High Very High Very High
Lung Cancer 282 84.56 Quite High
Breast Cancer 23 82.96 Quite High
Adenocarcinoma 49 82.76 Quite High
Repression 12 79.72 Quite High
Non-small-cell Lung Cancer 120 77.08 Quite High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
We observed an initial decrease in Nrf2 protein in MDA-MB-231 cells and UROtsa cells at 56 ?
Negative_regulation (decrease) of Nrf2 protein in MDA-MB-231
1) Confidence 0.59 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.64 Pain Relevance 0
This decrease in Nrf2 protein level in response to high doses of oridonin is not due solely to cell toxicity because Keap1 or ?
Negative_regulation (decrease) of Nrf2 protein associated with toxicity
2) Confidence 0.43 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.63 Pain Relevance 0
Nevertheless, reduction of the Nrf2 protein was significantly more substantial, indicating that reduction of Nrf2 at high doses may not be due solely to reduced cell number.
Negative_regulation (reduction) of Nrf2 protein
3) Confidence 0.43 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.12 Pain Relevance 0
Nevertheless, reduction of the Nrf2 protein was significantly more substantial, indicating that reduction of Nrf2 at high doses may not be due solely to reduced cell number.
Negative_regulation (reduction) of Nrf2
4) Confidence 0.43 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.11 Pain Relevance 0
Based on the important role of Nrf2 in cell survival, it is conceivable that Nrf2 has to be repressed before the execution of cell death.
Negative_regulation (repressed) of Nrf2 associated with death
5) Confidence 0.43 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.63 Pain Relevance 0
Ubiquitination of endogenous Nrf2 in UROtsa cells was blocked by oridonin or tBHQ treatment (Figure 3A, right panel).
Negative_regulation (blocked) of Nrf2
6) Confidence 0.43 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.18 Pain Relevance 0
If future experiments verify that enhanced activation of NRF2 is a key cause of chemoresistance and poor prognosis, one could envision development of specific siRNA or small molecule inhibitors of NRF2 for treatment of patients with tumors resistant to chemotherapy.


Negative_regulation (inhibitors) of NRF2 associated with cancer
7) Confidence 0.41 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.73 Pain Relevance 0
If such studies confirm that high NRF2 activity (either through mutation or by some other route) is often associated with a poor tumor response to chemotherapy, then the development of NRF2 inhibitors might help to improve treatment outcomes in patients with chemotherapy-resistant tumors.


Negative_regulation (inhibitors) of NRF2 associated with cancer
8) Confidence 0.41 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 0.91 Pain Relevance 0
Importantly, all of the three mutants of KEAP1 could not repress the activity of NRF2, whereas overexpression of WT-KEAP1 completely abolished the NRF2-mediated ARE reporter activity (Figure 6A).
Neg (not) Negative_regulation (repress) of NRF2
9) Confidence 0.41 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.84 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 (regulator) of Nrf2
10) Confidence 0.41 Published 2002 Journal Free Radic. Biol. Med. Section Abstract Doc Link 11909699 Disease Relevance 0.05 Pain Relevance 0.17
KEAP1 constitutively suppresses NRF2 activity in the absence of stress; however, oxidants, xenobiotics, and electrophiles hamper the KEAP1-mediated proteasomal degradation of NRF2, which results in increased nuclear accumulation and, in turn, the transcriptional induction of target genes that ensure cell survival. [7,23] Recently, Padmanabhan et al. [24] reported a heterozygous somatic mutation (G430C) in KEAP1 in one lung cancer tumor and a G364C mutation in an adenocarcinoma and a small cell lung cancer cell line.
Negative_regulation (suppresses) of NRF2 in lung associated with adenocarcinoma, stress, lung cancer and cancer
11) Confidence 0.41 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.66 Pain Relevance 0
Importantly, all of the three mutants of KEAP1 could not repress the activity of NRF2, whereas overexpression of WT-KEAP1 completely abolished the NRF2-mediated ARE reporter activity (Figure 6A).
Negative_regulation (abolished) of NRF2
12) Confidence 0.41 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.77 Pain Relevance 0
Furthermore, RNA interference (RNAi) depletion of SQSTM1 resulted in an increase in the protein level of Keap1 and a concomitant decrease in the protein level of Nrf2 in the absence of changes in Keap1 or Nrf2 mRNA levels.
Negative_regulation (decrease) of Nrf2
13) Confidence 0.31 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2878012 Disease Relevance 0 Pain Relevance 0
In light of the observation of Komatsu and colleagues that ectopic expression of SQSTM1 causes a decrease in the ubiquitination of Nrf2, and in turn an increase in the total cellular level of the transcription factor (23), it is plausible that the decrease in total cellular level of Nrf2 following siRNA depletion of SQSTM1 reported here is due to an increase in Keap1-directed ubiquitination of Nrf2, facilitated by the higher basal level of Keap1.
Negative_regulation (decrease) of Nrf2
14) Confidence 0.31 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878012 Disease Relevance 0.07 Pain Relevance 0
Given that siRNA depletion of SQSTM1 resulted in a decrease in the basal protein level of Nrf2, we hypothesized that this would correspond to a decrease in the capacity of Nrf2-regulated cell defense processes.
Negative_regulation (decrease) of Nrf2
15) Confidence 0.23 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878012 Disease Relevance 0 Pain Relevance 0
Notably, the reduction in the basal level of Nrf2 upon siRNA depletion of SQSTM1 did not compromise the inducibility of the Keap1-Nrf2 pathway, as demonstrated by the marked accumulation of Nrf2 in both si-CON and si-SQSTM1 m3-transfected Hepa-1c1c7 cells exposed to iodoacetamide or tert-butylhydroquinone for 1 h (Fig. 3E).
Negative_regulation (reduction) of Nrf2 in Hepa-1c1c7
16) Confidence 0.23 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878012 Disease Relevance 0 Pain Relevance 0
The decreased level of Nrf2 in cells depleted of SQSTM1 by RNAi was associated with decreases in the mRNA levels, protein levels, and function of several Nrf2-regulated cell defense genes.
Negative_regulation (decreased) of Nrf2
17) Confidence 0.23 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2878012 Disease Relevance 0 Pain Relevance 0
The decreased level of Nrf2 in cells depleted of SQSTM1 by RNAi was associated with decreases in the mRNA levels, protein levels, and function of several Nrf2-regulated cell defense genes.
Negative_regulation (decreases) of Nrf2
18) Confidence 0.23 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2878012 Disease Relevance 0 Pain Relevance 0
In the absence of chemical/oxidative stress, the activity of Nrf2 is repressed by Keap1, a cysteine-rich protein that acts as a substrate adaptor for the cullin 3-dependent ubiquitination of Nrf2, thereby directing the transcription factor for proteasomal degradation (5–7).
Negative_regulation (repressed) of Nrf2 associated with stress
19) Confidence 0.23 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878012 Disease Relevance 0.37 Pain Relevance 0

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