Abstract
Elevated temperatures activate the survival promoters Akt and heat shock factor-1 (HSF-1), a transcription factor that induces the expression of heat shock proteins (HSPs), such as HSP-70. Because neuronal mechanisms controlling these responses are not known, these were investigated in human neuroblastoma SH-SY5Y cells. Heat shock (45°C) rapidly activated Akt, extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and p38, but only Akt was activated in a phosphatidylinositol 3-kinase (Pl-3K)-dependent manner, as the Pl-3K inhibitors LY294002 and wortmannin blocked Akt activation, but not ERK1/2 or p38 activation. Akt activation was not blocked by inhibition of p38 or ERK1/2, indicating the independence of these signaling systems. Heat shock treatment also caused a rapid increase in HSF-1 DNA binding activity that was partially dependent on Pl-3K activity, as both the Pl-3K inhibitors attenuated this response. Because Akt inhibits glycogen synthase kinase-3β (GSK-3β), an enzyme that facilitates cell death, we tested if GSK-3β is a negative regulator of HSF-1 activation. Overexpression of GSK-3β impaired heat shock-induced activation of HSF-1, and also reduced HSP-70 production, which was partially restored by the GSK-3β inhibitor lithium. Thus, heat shock-induced activation of Pl-3K and the inhibitory effect of GSK-3β on HSF-1 activation and HSP-70 expression imply that Akt-induced inhibition of GSK-3β contributes to the activation of HSF-1.
| Original language | English |
|---|---|
| Pages (from-to) | 2401-2408 |
| Number of pages | 8 |
| Journal | Journal of Neurochemistry |
| Volume | 75 |
| Issue number | 6 |
| DOIs | |
| State | Published - Nov 23 2000 |
| Externally published | Yes |
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Keywords
- Akt
- Glycogen synthase kinase-3β
- Heat shock factor-1
- Heat shock protein-70
- Lithium
- Phosphatidylinositol 3-kinase
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience
Cite this
Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3β in the regulation of HSF-1 activity. / Bijur, Gautam N.; Jope, Richard S.
In: Journal of Neurochemistry, Vol. 75, No. 6, 23.11.2000, p. 2401-2408.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3β in the regulation of HSF-1 activity
AU - Bijur, Gautam N.
AU - Jope, Richard S
PY - 2000/11/23
Y1 - 2000/11/23
N2 - Elevated temperatures activate the survival promoters Akt and heat shock factor-1 (HSF-1), a transcription factor that induces the expression of heat shock proteins (HSPs), such as HSP-70. Because neuronal mechanisms controlling these responses are not known, these were investigated in human neuroblastoma SH-SY5Y cells. Heat shock (45°C) rapidly activated Akt, extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and p38, but only Akt was activated in a phosphatidylinositol 3-kinase (Pl-3K)-dependent manner, as the Pl-3K inhibitors LY294002 and wortmannin blocked Akt activation, but not ERK1/2 or p38 activation. Akt activation was not blocked by inhibition of p38 or ERK1/2, indicating the independence of these signaling systems. Heat shock treatment also caused a rapid increase in HSF-1 DNA binding activity that was partially dependent on Pl-3K activity, as both the Pl-3K inhibitors attenuated this response. Because Akt inhibits glycogen synthase kinase-3β (GSK-3β), an enzyme that facilitates cell death, we tested if GSK-3β is a negative regulator of HSF-1 activation. Overexpression of GSK-3β impaired heat shock-induced activation of HSF-1, and also reduced HSP-70 production, which was partially restored by the GSK-3β inhibitor lithium. Thus, heat shock-induced activation of Pl-3K and the inhibitory effect of GSK-3β on HSF-1 activation and HSP-70 expression imply that Akt-induced inhibition of GSK-3β contributes to the activation of HSF-1.
AB - Elevated temperatures activate the survival promoters Akt and heat shock factor-1 (HSF-1), a transcription factor that induces the expression of heat shock proteins (HSPs), such as HSP-70. Because neuronal mechanisms controlling these responses are not known, these were investigated in human neuroblastoma SH-SY5Y cells. Heat shock (45°C) rapidly activated Akt, extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and p38, but only Akt was activated in a phosphatidylinositol 3-kinase (Pl-3K)-dependent manner, as the Pl-3K inhibitors LY294002 and wortmannin blocked Akt activation, but not ERK1/2 or p38 activation. Akt activation was not blocked by inhibition of p38 or ERK1/2, indicating the independence of these signaling systems. Heat shock treatment also caused a rapid increase in HSF-1 DNA binding activity that was partially dependent on Pl-3K activity, as both the Pl-3K inhibitors attenuated this response. Because Akt inhibits glycogen synthase kinase-3β (GSK-3β), an enzyme that facilitates cell death, we tested if GSK-3β is a negative regulator of HSF-1 activation. Overexpression of GSK-3β impaired heat shock-induced activation of HSF-1, and also reduced HSP-70 production, which was partially restored by the GSK-3β inhibitor lithium. Thus, heat shock-induced activation of Pl-3K and the inhibitory effect of GSK-3β on HSF-1 activation and HSP-70 expression imply that Akt-induced inhibition of GSK-3β contributes to the activation of HSF-1.
KW - Akt
KW - Glycogen synthase kinase-3β
KW - Heat shock factor-1
KW - Heat shock protein-70
KW - Lithium
KW - Phosphatidylinositol 3-kinase
UR - http://www.scopus.com/inward/record.url?scp=0033773645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033773645&partnerID=8YFLogxK
U2 - 10.1046/j.1471-4159.2000.0752401.x
DO - 10.1046/j.1471-4159.2000.0752401.x
M3 - Article
C2 - 11080191
AN - SCOPUS:0033773645
VL - 75
SP - 2401
EP - 2408
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 6
ER -