Hsp72-Mediated Suppression of c-Jun N-Terminal Kinase Is Implicated in Development of Tolerance to Caspase-Independent Cell Death

Gabai, Vladimir L.; Yaglom, Julia A.; Volloch, Vladimir; Meriin, Anatoli B.; Force, Thomas; Koutroumanis, Maria; Massie, Bernard; Mosser, Dick D.; Sherman, Michael Y.

doi:10.1128/mcb.20.18.6826-6836.2000

Cited by 152 publications

(128 citation statements)

References 48 publications

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“…Although interaction between hsp70 and bax could regulate bax and was observed in a single report (61), other investigators have not (1,23). Alternatively, hsp70 could inhibit the activation of Jun-N-terminal kinase (23,62), potentially reducing its ability to recruit bax to the mitochondrial membrane (63). In addition to preventing bax activation, bcl2 may be an attractive target for protection by hsp70, since it antagonizes the effect of bax on the mitochondrial membrane and reduces both mitochondrial AIF release (64,65) and cytochrome c-dependent caspase activation (30,64,66).…”

Section: Discussionmentioning

confidence: 99%

Distinct hsp70 Domains Mediate Apoptosis-inducing Factor Release and Nuclear Accumulation

Ruchalski

Mao

et al. 2006

Journal of Biological Chemistry

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112

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Although hsp70 antagonizes apoptosis-inducing factor (AIF)-mediated cell death, the relative importance of preventing its release from mitochondria versus sequestering leaked AIF in the cytosol remains controversial. To dissect these two protective mechanisms, hsp70 deletion mutants lacking either the chaperone function (hsp70-⌬EEVD) or ATPase function (hsp70-⌬ATPase) were selectively overexpressed before exposing cells to a metabolic inhibitor, an insult sufficient to cause mitochondrial AIF release, nuclear AIF accumulation, and apoptosis. Compared with empty vector, overexpression of wild type human hsp70 inhibited bax activation and reduced mitochondrial AIF release after injury. In contrast, mutants lacking either the chaperone function (hsp70-⌬EEVD) or the ATP hydrolytic domain (hsp70-⌬ATPase) failed to prevent mitochondrial AIF release. Although hsp70-⌬EEVD did not inhibit bax activation or mitochondrial membrane injury after cell stress, this hsp70 mutant co-immunoprecipitated with leaked AIF in injured cells and decreased nuclear AIF accumulation. In contrast, hsp70-⌬ATPase did not interact with AIF either in intact cells or in a cell-free system and furthermore, failed to prevent nuclear AIF accumulation. These results demonstrate that mitochondrial protection against bax-mediated injury requires both intact chaperone and ATPase functions, whereas the ATPase domain is critical for sequestering AIF in the cytosol.Disruption of the outer mitochondrial membrane releases toxic proteins, including cytochrome c and apoptosis-inducing factor (AIF) 3 that activate caspase-dependent and -independent pathways responsible for apoptotic cell death. In a prior study in our laboratory, neither a pancaspase inhibitor nor a specific caspase 3 inhibitor completely prevented apoptosis in renal cells exposed to metabolic inhibitors (1), suggesting that at least a portion of the observed apoptosis is mediated by non-caspase-dependent factors including AIF. Nuclear translocation of AIF activates endogenous endonucleases leading to degradation of native DNA into 50-kilobase fragments, peripheral chromatin condensation, and nuclear shrinkage (2-4) that is sufficient to cause apoptosis (5, 6). AIF mediates apoptosis in multiple cell lines after diverse insults including ischemia (7-10), oxidant stress (11), ethanol (12), or p53 exposure (8).AIF is synthesized in the cytosol as a 67-kDa precursor protein that contains a mitochondrial-localizing sequence (13,14). After being imported into mitochondria, the mitochondrial-localizing sequence is cleaved, resulting in the accumulation of the mature, 57-kDa AIF protein (13). Under normal circumstances AIF may facilitate electron transport, since it exhibits robust oxidoreductase activity (14). AIF-mediated cell death is a two-step process that involves initial release from the intramembranous mitochondrial space into the cytosol followed by nuclear uptake and accumulation (5,13,15,16).hsp70, an inducible cytoprotectant protein, antagonizes apoptosis by interfering with multiple ch...

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Section: Discussionmentioning

confidence: 99%

Distinct hsp70 Domains Mediate Apoptosis-inducing Factor Release and Nuclear Accumulation

Ruchalski

Mao

et al. 2006

Journal of Biological Chemistry

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112

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“…Another way in which Hsp may act to promote survival and prevent cell death is through suppression of other apoptotic signaling pathways. Several laboratories have provided evidence indicating that Hsp70 can inhibit JNK activity and thereby inhibit JNK-mediated apoptosis (Gabai et al, 1997(Gabai et al, , 2000bPark et al, 2001a). Two different mechanisms may contribute to this function.…”

Section: How Do Hsp Protect Cells Against Oxidative Damage?mentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,100

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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“…When exposed to severe heat shock, human fibroblasts underwent a death that was morphologically indistinguishable from apoptosis but independent of caspases. However, these fibroblasts could survive such heat shock if JNK was inhibited (19). On the contrary, if ERK or Akt kinases were inhibited, much milder heat shock, not toxic to control cells, killed almost 100% of the cell population (19) via a caspase-independent apoptosis.…”

Section: Cell Death and Survival Pathways Activated By Heat Shockmentioning

confidence: 99%

“…Expression of HSP72 dramatically reduces activation of JNK by heat shock (18,38), and this effect of HSP72 appears to be critical for inhibition of apoptosis in nontransformed cells (18). Beside classical caspase-dependent apoptosis, suppression of JNK by HSP72 also appears to play an important role in caspase-independent death pathways (17), e.g., heatinduced apoptosis of human fibroblasts (19) or heatinduced clonogenic cell death (67).…”

Section: Hsps Control Apoptotic Signaling Pathwaysmentioning

confidence: 99%

Invited Review: Interplay between molecular chaperones and signaling pathways in survival of heat shock

Gabai

Sherman

2002

Journal of Applied Physiology

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158

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. Invited Review: Interplay between molecular chaperones and signaling pathways in survival of heat shock. J Appl Physiol 92: 1743-1748, 2002; 10.1152/ japplphysiol.01101.2001.-Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH 2-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant. thermotolerance; heat shock proteins; mitogen-activated protein kinases; apoptosis EXPOSURE OF MAMMALIAN CELLS to elevated temperatures (heat shock) triggers several signaling pathways, some that facilitate cell survival and some that initiate cell death programs. The outcome of a cell's exposure to heat shock may be either a development of a state of tolerance to heat shock and other stresses, if survival pathways prevail, or cell death, if death pathways prevail. The first-discovered survival pathway activated by heat shock was the heat shock response, i.e., induction of heat shock proteins (HSPs) such as HSP72, HSP27, HSP40, and HSP90, mediated by heat shock transcription factors (HSFs) (see Ref. 46 for a recent review). HSPs confer thermotolerance as well as resistance to other stresses, such as ethanol, heavy metals, oxidative stress, ischemia, or tumor necrosis factor (see Refs. 16 and 23 for review).Heat shock causes extensive denaturation and aggregation of intracellular proteins; therefore, early studies focused on the search of labile critical proteins whose damage when exposed to heat shock may lead to cell death (see Refs. 25 and 26 for review). Among major proteins easily denatured and aggregated in heat-shocked cells were components of nuclear matrix and cytoskeleton (2,25,26,31,41), although it should be noted that there are no data directly linking damage of these proteins to cell death. HSPs serve as molecular chaperones in refolding, disaggregation, and degradation of damaged polypeptides (see Refs. 15 and 21 for review). In fact, aggregation of nuclear proteins as well as a reporter enzyme (firefly luciferase) after heat shock was reduced in thermotolerant cells expressing HSPs, and these cells demonstrated faster solubilization of aggregated proteins during the recovery period (2,26,42,53). Furthermore, expression of HSP72 (the major inducible member of the HSP70 family) alone was sufficient to reduce nuclear protein aggregation and accelera...

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Hsp72-Mediated Suppression of c-Jun N-Terminal Kinase Is Implicated in Development of Tolerance to Caspase-Independent Cell Death

Cited by 152 publications

References 48 publications

Distinct hsp70 Domains Mediate Apoptosis-inducing Factor Release and Nuclear Accumulation

Distinct hsp70 Domains Mediate Apoptosis-inducing Factor Release and Nuclear Accumulation

Cellular response to oxidative stress: Signaling for suicide and survival*

Invited Review: Interplay between molecular chaperones and signaling pathways in survival of heat shock

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