Heat Shock Proteins 70 and 90 Increase Calcineurin Activity in Vitro through Calmodulin-Dependent and Independent Mechanisms

Someren, J S; Faber, Lee E.; Klein, Janet D.; Tumlin, James A.

doi:10.1006/bbrc.1999.0800

Cited by 56 publications

(42 citation statements)

References 26 publications

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“…However, this equilibrium shift is not sufficient for the activation of calcineurin because neither canavanine nor heat shock activated calcineurin (unpublished observations). The present finding is consistent in part with the report by Someren et al (42), in that Hsp90 interacts with the catalytic subunit of calcineurin in vivo. However, as described above, we observed that HSP90 stabilizes, but does not activate, calcineurin; this is inconsistent with the notion that HSP90 increases calcineurin activity in a dose-dependent manner (42).…”

Section: Discussionsupporting

confidence: 94%

Role of HSP90 in Salt Stress Tolerance via Stabilization and Regulation of Calcineurin

Imai

Yahara

2000

Molecular and Cellular Biology

115

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The role of HSP90 in stress tolerance was investigated in Saccharomyces cerevisiae. Cells showing 20-fold overexpression of Hsc82, an HSP90 homologue in yeast, were hypersensitive to high-NaCl or H-LiCl stresses. Hsc82-overexpressing cells appeared similar to calcineurin-defective cells in salt sensitivity and showed reduced levels of calcineurin-dependent gene expression. Co-overexpression of Cna2, the catalytic subunit of calcineurin, suppressed the hypersensitivity. Cna2 and Hsc82 coimmunoprecipitated from control cells grown under normal conditions but not from stressed cells. In contrast, coimmunoprecipitation was detected with Hsc82-overexpressing cells even after exposure to stresses. Cna2 immune complexes from stressed control cells showed a significant level of calcineurin activity, whereas those from stressed Hsc82-overexpressing cells did not. Treatment of extracts from Hsc82-overexpressing cells with Ca 2؉ -calmodulin increased the calcineurin activity associated with Cna2 immune complexes. Geldanamycin, an inhibitor of HSP90 abolished the coimmunoprecipitation but did not activate calcineurin. When the expression level of Hsc82 decreased to below 30% of the normal level, cells also became hypersensitive to salt stress. In these cells, the amount of Cna2 was reduced, likely as a result of degradation. The present results showed that Hsc82 binds to and stabilizes Cna2 and that dissociation of Cna2 from Hsc82 is necessary for its activation.

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Section: Discussionsupporting

confidence: 94%

Role of HSP90 in Salt Stress Tolerance via Stabilization and Regulation of Calcineurin

Imai

Yahara

2000

Molecular and Cellular Biology

115

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“…Candidates for such factors include RCAN1 (regulator of calcineurin 1) 13 and heat shock protein-90. 14 Relationships among ER stress, Jak2 signaling, and antiinfarct tolerance of the myocardium in the diabetic heart are complex. Our previous studies have shown that PI3K-Akt and ERK pathways downstream of the EPO receptor have complementary roles in cardioprotection.…”

Section: Discussionmentioning

confidence: 99%

Short Communication: Angiotensin II Type 1 Receptor–Mediated Upregulation of Calcineurin Activity Underlies Impairment of Cardioprotective Signaling in Diabetic Hearts

Hotta

Miura²,

Miki³

et al. 2010

Circulation Research

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Rationale: The diabetic heart is resistant to ischemic preconditioning because of diabetes-associated impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. The mechanism by which PI3K-Akt signaling is impaired by diabetes remains unclear. Objective: Here, we examined the hypothesis that phosphorylation of iabetes mellitus not only accelerates atherosclerosis of the coronary artery but also induces functional and structural abnormalities in the myocardium. In addition, recent studies have shown that myocardial response to ischemic preconditioning (IPC) and its mimetics is blunted or lost in diabetic hearts. 1-3 Protection afforded by IPC is triggered by activation of G protein-coupled receptors 5 and impaired activation of phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) in models of diabetes mellitus have been reported. 1-3 Our recent study 3 showed impaired activation of Jak2 and endoplasmic reticulum (ER) stress-mediated disruption of signaling from ERK to glycogen synthase kinase (GSK)-3␤ in diabetic hearts. However, the mechanism by which Jak2-mediated signaling is disabled in diabetic hearts remains unclear. In the present study, we tested the hypothesis that Jak2-mediated protection is impaired in diabetic myocardium by an angiotensin II type 1 (AT 1 ) receptor-mediated mechanism via upregulation of SOCS3 (suppressor of cytokine signaling 3)-Jak2 interaction or calcineurin. MethodsMale Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, which spontaneously develop obesity and type 2 diabetes, and their controls (Long-Evans-Tokushima-Otsuka [LETO] rats) were used. Preparation of myocardial infarction, immunoblotting, quantitative real-time RT-PCR, calcineurin activity assay, and determination of insulin sensitivity were performed by standard methods (see the expanded Methods section in the Online Data Supplement, available at

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“…Thus, PPs appear as key linker molecules between the cellular effects of TNFa, the activation of HSF1/hsp70 stress responses and cellular susceptibility to apoptosis. Several points of evidence support this concept: (i) PPs PP1/PP2a and PP2b can be activated by TNFa, 29,39 (ii) activation of these PPs increases susceptibility to apoptotic cell death, 28,29 (iii) activation of PP1/PP2a and PP2b (calcineurin) as well as elevated intracellular calcium levels inhibit phosphorylation of HSF1 and thus activation of the HSF1/hsp70 stress response, [40][41][42] (iv) hsp70, which acts in a negative-feedback loop on HSF1 activation, 18 induces PP1/PP2a as well as PP2b and thus blocks continuing activation of HSF1 43,44 and (v) ERK and NF-kB signaling, which maintained a certain responsiveness of HSF1/hsp70 and also protected cells from apoptotic death, is a concurring mechanism to PPs, since their mutual inhibition has been repeatedly demonstrated. 45,46 In summary, the data presented provide insights into the interplay of signals essential for cell survival, stress resistance and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

TNFα mediates susceptibility to heat-induced apoptosis by protein phosphatase-mediated inhibition of the HSF1/hsp70 stress response

Schett

et al. 2003

Cell Death Differ

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TNFa uniquely combines proinflammatory features with a proapoptotic potential. Activation of HSF1 followed by induction of hsp70 is part of a stress response, which protects cells from apoptosis. Herein, the effects of TNFa on the hsp70 stress response were investigated. TNFa caused transient downregulation of HSF1 activation and hsp70 synthesis, leading to increased sensitivity to heat-induced apoptosis. Blockade of TNF-R1, but not TNF-R2, as well as inhibition of protein phosphatases PP1/PP2a and PP2b completely blocked this effect. In contrast, blockade of MAPK/SAPK-, NF-jB (NF-kappaB)-, and PKC-pathways as well as the caspase cascade did not prevent downregulation of HSF1/hsp70. These data demonstrate that TNFa transiently inhibits the hsp70 stress response via TNF-R1 and activation of protein phosphatases. The price of inhibition of an essential cellular stress response is increased sensitivity to apoptotic cell death.

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Heat Shock Proteins 70 and 90 Increase Calcineurin Activity in Vitro through Calmodulin-Dependent and Independent Mechanisms

Cited by 56 publications

References 26 publications

Role of HSP90 in Salt Stress Tolerance via Stabilization and Regulation of Calcineurin

Role of HSP90 in Salt Stress Tolerance via Stabilization and Regulation of Calcineurin

Short Communication: Angiotensin II Type 1 Receptor–Mediated Upregulation of Calcineurin Activity Underlies Impairment of Cardioprotective Signaling in Diabetic Hearts

TNFα mediates susceptibility to heat-induced apoptosis by protein phosphatase-mediated inhibition of the HSF1/hsp70 stress response

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