INT203839

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Context Info
Confidence 0.32
First Reported 2007
Last Reported 2011
Negated 0
Speculated 0
Reported most in Body
Documents 18
Total Number 18
Disease Relevance 4.36
Pain Relevance 2.22

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

RNA binding (Eif2ak2) nucleus (Eif2ak2) intracellular (Eif2ak2)
translation (Eif2ak2) kinase activity (Eif2ak2)
Anatomy Link Frequency
macrophages 3
MEFs 2
intermediary 1
peritoneal macrophages 1
reticulum 1
Eif2ak2 (Mus musculus)
Pain Link Frequency Relevance Heat
tolerance 588 98.60 Very High Very High Very High
addiction 14 95.36 Very High Very High Very High
Inflammation 187 94.88 High High
Central nervous system 24 94.08 High High
agonist 42 93.96 High High
cytokine 167 75.00 Quite High
dopaminergic neurodegeneration 1 72.56 Quite High
Dopamine 61 63.40 Quite High
palliative 14 62.36 Quite High
Potency 104 57.28 Quite High
Disease Link Frequency Relevance Heat
Stress 22 97.84 Very High Very High Very High
Apoptosis 46 97.04 Very High Very High Very High
INFLAMMATION 232 94.88 High High
Targeted Disruption 42 92.60 High High
Toxicity 57 90.52 High High
Pressure And Volume Under Development 5 80.64 Quite High
Hepatotoxicity 83 79.28 Quite High
Neurodegenerative Disease 17 78.12 Quite High
Sepsis 141 75.20 Quite High
Volume Depletion And Dehydration 1 71.92 Quite High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
Although the canonical model for PKR activation requires its interaction with exogenous RNAs not known to be produced downstream of TLR ligation, multiple studies have reported roles for PKR in the cellular response to LPS.
Positive_regulation (activation) of PKR
1) Confidence 0.32 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.20 Pain Relevance 0.26
One candidate intermediary for linking TLRs to PKR activation is the PKR-interacting protein PACT/RAX, known to activate PKR under diverse conditions of cellular stress independently of RNA (41, 42).
Positive_regulation (activation) of PKR in intermediary associated with stress
2) Confidence 0.23 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.15 Pain Relevance 0.15
This result was surprising because our previous observation that proteosome inhibition could restore activation in tolerance (Fig. 3A) had led us to expect that PKR would be inducibly ubiquitinated to a greater degree in tolerant cells, leading to subsequent degradation and, thus, explaining the failure in observing PKR activation in tolerized macrophages.
Positive_regulation (activation) of PKR in macrophages associated with tolerance
3) Confidence 0.23 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0 Pain Relevance 0.05
Our results show that PKR activation is not a feature of all TLRs, as evidenced by the fact that PKR is activated by TLR4 and TLR3 but not by TLR2.
Positive_regulation (activation) of PKR
4) Confidence 0.23 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.10 Pain Relevance 0.16
Interestingly, we did not observe substantial PKR activation by the TLR2 ligand S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-Ser-Lys4-OH (P3C), and its ability to induce ERK phosphorylation was slightly delayed and less robust than that induced by LPS (Fig. 1, middle).
Positive_regulation (activation) of PKR
5) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0 Pain Relevance 0
Stimulation of wild-type, naive MEFs produced a modest and transient activation of PKR (Fig. 5E).
Positive_regulation (activation) of PKR in MEFs
6) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.15 Pain Relevance 0.03
We also show that total PKR levels are elevated in LPS-tolerant murine macrophages but not in MEFs, a fact that may reflect the far greater LPS sensitivity of macrophages compared to that of embryonic fibroblasts.
Positive_regulation (elevated) of PKR in fibroblasts
7) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.09 Pain Relevance 0.16
Delineation of the precise TLR-inducible signaling complexes leading to PKR activation will be a compelling avenue for investigation and should expand our understanding of TLR signaling.
Positive_regulation (activation) of PKR
8) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.14 Pain Relevance 0.16
As it is possible that tolerant macrophages may simply exhibit delayed kinetics of PKR activation, additional time courses of activation to 180 min were carried out, with no LPS-mediated increase in PKR activity (data not shown).
Positive_regulation (activation) of PKR in macrophages
9) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0 Pain Relevance 0.04
Remarkably, PKR activity was dramatically enhanced and maximal in unstimulated SOCS-1?
Positive_regulation (enhanced) of PKR
10) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.16 Pain Relevance 0.03
Remarkably, PKR activity was dramatically enhanced and maximal in unstimulated SOCS-1?
Positive_regulation (maximal) of PKR
11) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0.16 Pain Relevance 0.04
We confirmed that PKR was activated by LPS stimulation in naive, medium-pretreated macrophages (Fig. 2, naive).
Positive_regulation (activated) of PKR in macrophages
12) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0 Pain Relevance 0.05
Primary peritoneal macrophages were stimulated with ligands for TLRs that differentially utilize different adapter combinations (e.g., TLR2 [TIRAP/MyD88], TLR3 [TRIF only], or TLR4 [TIRAP/MyD88 and TRAM/TRIF]) over a 90-min time course, and the activation of PKR was measured by phosphospecific Western analysis (Fig. 1).
Positive_regulation (activation) of PKR in peritoneal macrophages
13) Confidence 0.22 Published 2010 Journal mBio Section Body Doc Link PMC2962435 Disease Relevance 0 Pain Relevance 0.03
In tolerance, the kinetics of this differential Ub is altered, resulting in a predominance of K48-linked chains, concomitant with a loss of PKR activation.
Positive_regulation (activation) of PKR associated with tolerance
14) Confidence 0.22 Published 2010 Journal mBio Section Abstract Doc Link PMC2962435 Disease Relevance 0.40 Pain Relevance 0.42
PKR is activated by binding of dsRNA to distinct dsRNA binding domains which serve as allosteric inhibitors of the kinase domain (47,48).
Positive_regulation (activated) of PKR
15) Confidence 0.16 Published 2007 Journal Nucleic Acids Research Section Body Doc Link PMC1802611 Disease Relevance 0.60 Pain Relevance 0.06
 : PKR, which is activated by binding of double stranded RNA (dsRNA); GCN2, which is activated by amino acid deprivation; HRI, which is activated by low heme levels; and PERK, which responds to stress in the endoplasmic reticulum.
Positive_regulation (activated) of PKR in reticulum associated with stress
16) Confidence 0.12 Published 2007 Journal Nucleic Acids Research Section Body Doc Link PMC1802611 Disease Relevance 0.65 Pain Relevance 0
induces microglial expression of iNOS and several key subunits of NADPH oxidase [126], as well as the IFN-inducible double-stranded RNA-activated kinase, PKR [127].
Positive_regulation (inducible) of PKR
17) Confidence 0.06 Published 2011 Journal Parkinson's Disease Section Body Doc Link PMC3018622 Disease Relevance 0.69 Pain Relevance 0.30
In addition, DAI-1, previously named DLM-1 or Z-DNA binding protein 1, has been identified as a cytoplasmic receptor that senses and is activated by DNA, leading to type I IFN gene induction [31].
Positive_regulation (induction) of type I IFN gene
18) Confidence 0.04 Published 2009 Journal Respir Res Section Body Doc Link PMC2761862 Disease Relevance 0.89 Pain Relevance 0.28

General Comments

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