INT256696

Context Info Confidence 0.66 First Reported 2009 Last Reported 2009 Negated 1 Speculated 2 Reported most in Body Documents 1 Total Number 21 Disease Relevance 9.14 Pain Relevance 0.17

endoplasmic reticulum (Wfs1) neurological system process (Wfs1)

Anatomy Link Frequency neuronal 2 upper 2 SH-SY5Y 1 Wfs1 (Mus musculus)

Pain Link Frequency Relevance Heat depression 63 91.32 anticonvulsant 21 9.68 gABA 84 7.16 Migraine 21 5.00 Neurotransmitter 21 5.00 GABAergic 21 5.00

Disease Link Frequency Relevance Heat Stress 441 99.74 Manic Depressive Disorder 399 98.48 Depression 63 91.32 Oxidative Phosphorylation Disease 63 85.16 Psychosis 21 82.16 Deafness 21 76.92 Optic Atrophy 21 76.40 Diabetes Mellitus 21 75.80 Diabetes Insipidus 21 75.04 Convulsion 42 5.80

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

Other unknown transcription factors induced by XBP-1 or interacted with XBP-1 may have a function in the activation of WFS1 promoter.

Positive_regulation (activation) of WFS1

1) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.39 Pain Relevance 0

Collectively, these results indicate that valproate can strongly activate the WFS1 promoter together with XBP-1 specifically in neuronal cells.

Positive_regulation (activate) of WFS1 in neuronal

2) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0 Pain Relevance 0

The upregulation of WFS1 by valproate is probably regulated by the same element because the promoter lacking this sequence, pGL3-WFS1-short, did not respond to valproate (Figure 2).

Positive_regulation (upregulation) of WFS1

3) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.35 Pain Relevance 0

phosphorylation levels (Figure 1A upper panel), raising the possibility that WFS1 upregulation by valproate is not regulated by the ER stress signaling network.

Positive_regulation (upregulation) of WFS1 in upper associated with stress

4) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.69 Pain Relevance 0

We were therefore interested in determining whether this WFS1 promoter can be activated by valproate treatment.

Positive_regulation (activated) of WFS1

5) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.45 Pain Relevance 0

Figure 1B shows that expression levels of these ER stress markers did not change by valproate, indicating that valproate specifically upregulates WFS1 without activating other components of ER stress signaling.

Positive_regulation (upregulates) of WFS1 associated with stress

6) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.57 Pain Relevance 0

It has been postulated that XBP-1 is important in activating the WFS1 promoter in SH-SY5Y cells [22].

Positive_regulation (activating) of WFS1 in SH-SY5Y

7) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.23 Pain Relevance 0

Another mood stabilizer, lithium, did not increase WFS1 expression levels significantly in these cells (Figure 1A, lower panel).

Neg (not) Positive_regulation (increase) of WFS1

8) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.71 Pain Relevance 0.03

To determine whether PERK signaling is involved in WFS1 upregulation by valproate, we measured expression levels of phosphorylated eIF2?

Spec (whether) Positive_regulation (upregulation) of WFS1

9) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.72 Pain Relevance 0

Valproate increased WFS1 expression levels in a dose-dependent manner (Figure 3A, lanes 5 and 6, lower panels, input).

Positive_regulation (increased) of WFS1

10) Confidence 0.66 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.06 Pain Relevance 0

Downregulation of GRP94 may increase the amount of GRP94-free WFS1, leading to the enhancement of WFS1 function.

Positive_regulation (enhancement) of WFS1

11) Confidence 0.48 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.19 Pain Relevance 0

Valproate increased WFS1 protein expression levels in Neuro-2a cells with a peak at 24 hr (Figure 1A, upper panel).

Positive_regulation (increased) of WFS1 in upper

12) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.83 Pain Relevance 0.06

Valproate activates the WFS1 promoter and induces WFS1 mRNA expression in neuronal cells.

Positive_regulation (activates) of WFS1 in neuronal

13) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 1.34 Pain Relevance 0.09

Thus, the downregulation of GRP94 may have the same effect as the upregulation of WFS1.

Positive_regulation (upregulation) of WFS1

14) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.18 Pain Relevance 0

The modulation of ER stress through the activation of WFS1 may be part of valproate's action in bipolar disorder.

Positive_regulation (activation) of WFS1 associated with stress and manic depressive disorder

15) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.48 Pain Relevance 0

Valproate decreased the ratio between immunoprecipiated WFS1 and GRP94 in a dose-dependent manner (Figure 3B), suggesting that WFS1 dissociates from GRP94 and that GRP94-free WFS1 is increased with valproate.

Positive_regulation (increased) of WFS1

16) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.21 Pain Relevance 0

Therapeutic concentrations of valproate induce expression of WFS1 mRNA and activate the WFS1 promoter.

Positive_regulation (activate) of WFS1

17) Confidence 0.44 Published 2009 Journal PLoS ONE Section Abstract Doc Link PMC2607540 Disease Relevance 0.61 Pain Relevance 0

Valproate strongly activates the promoter region of WFS1 gene.

Positive_regulation (activates) of WFS1 gene

18) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.36 Pain Relevance 0

It is also possible that upregulation of WFS1 by valproate increases the ratio between GRP94-free WFS1 and GRP94-bound WFS1, leading to the activation of WFS1 (Figure 4).

Spec (possible) Positive_regulation (upregulation) of WFS1

19) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.17 Pain Relevance 0

We have previously shown that the minimum element for WFS1 promoter activation under ER stress conditions.

Positive_regulation (activation) of WFS1 associated with stress

20) Confidence 0.44 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2607540 Disease Relevance 0.37 Pain Relevance 0

General Comments

This test has worked.