Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase

Park, Hee Sae; Lee, Jae Seon; Huh, Sung Ho; Seo, Jeong Sun; Choi, Eui Ju

doi:10.1093/emboj/20.3.446

Cited by 297 publications

(239 citation statements)

References 67 publications

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“…Accordingly, HSP70 depletion is shown to sensitize PRO cell-free extracts to caspase activation by cytochrome c. Several other molecular mechanisms have been involved in the antiapoptotic e ect of HSP70, including inhibition of c-Jun N-terminal kinase (JNK) that contributes to cell death under certain conditions (Mosser et al, 1997;Park et al, 2001); interaction with AIF to prevent caspase-independent cell death (Ravagnan et al, 2001); prevention of cytochrome c release from the mitochondrion and refolding of proteins cleaved by e ector caspases (Jaattela et al, 1998). One or several of these mechanisms may account for the increased in vivo cell death induced by HSP70 depletion in PRO colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells

et al. 2001

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Expression of inducible heat shock protein 70 (HSP70) in tumor cells has been proposed to enhance their immunogenicity. However, HSP70 has also been demonstrated to prevent tumor cell death, a key process for the development of tumor cell immunogenicity. In the present study, we investigated the in¯uence of the HSP70 protein level on PRO colon cancer cell growth and immunogenicity in syngeneic BDIX rats and nude mice. These cells have a basal expression of HSP70 which can be substantially increased by heat shock. When injected subcutaneously in syngeneic animals, PRO cells do not induce any detectable immune response and give rise to progressive, metastatic and lethal tumors. Stable transfection of an anti-sense hsp70 cDNA in PRO cells (PRO-70AS cells) strongly decreased HSP70 expression and sensitized cell-free extracts to cytochrome c/dATPmediated activation of caspases. Subcutaneous injection of PRO-70AS cells induced tumors that rapidly regressed in syngeneic rats while they grew normally in nude mice. Syngeneic rats injected with PRO-70AS cells became protected against a further challenge with PRO cells. The tumor-speci®c immune response induced by HSP70-depleted PRO-70AS cells was associated with an increased rate of cell death in vivo. These PRO-70AS cells were also more sensitive to NO-mediated, caspasedependent, macrophage cytotoxicity in vivo. Altogether, these results indicate that reduced level of HSP70 expression in PRO-colon cancer cells results in the generation of a speci®c immune response by promoting cell death in vivo. Oncogene (2001) 20, 7478 ± 7485.

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Section: Discussionmentioning

confidence: 99%

Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells

et al. 2001

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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%

“…Sherman and colleagues have suggested that Hsp70 reduces JNK activity by increasing the rate of its dephosphorylation (Meriin et al, 1999;Volloch et al, 2000;Gabai et al, 2000a). An alternative mechanism is suggested by studies of Park et al (2001a) who provided evidence that Hsp70 binds to JNK to prevent its phosphorylation by upstream kinases. Importantly, the chaperone function of Hsp was not required for this effect.…”

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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“…On the other hand, if HSP72 acts as a suppressor of signal transduction, its refolding activity may be dispensable. Interestingly, the HSP72 mutant lacking the ATPase domain retains the ability to inhibit JNK (45,59,63) and protects fibroblasts from heat-induced killing (34,54,59). Because this mutant is unable to refold heat-damaged proteins (while being able to bind to them) (34,54), it appears that, at least in certain cell types, the JNK-inhibiting activity of HSP72 is sufficient for protection from heat-induced cell death.…”

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

158

109

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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 functions as a natural inhibitory protein of c-Jun N-terminal kinase

Cited by 297 publications

References 67 publications

Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells

Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells

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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