Heat Shock Protein 70 Inhibits Apoptosis Downstream of Cytochrome c Release and Upstream of Caspase-3 Activation

Li, Chunying; Lee, Jae‐Seon; Ko, Young‐Gyu; Kim, Jong‐il; Seo, Jong-Soo

doi:10.1074/jbc.m906383199

Cited by 431 publications

(287 citation statements)

References 57 publications

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“…Increased Hsp70 expression in tumours also correlates with evasion from apoptosis (Ciocca et al, 1993;Wei et al, 1995;Jaattela, 1999;Kaur et al, 2000). Hsp70 was further shown to inhibit the activation of procaspase-3, but not the activity of processed caspase-3 (Mosser et al, 1997;Li et al, 2000;Mosser et al, 2000;Saleh et al, 2000). Hsp70 was found to associate with Apaf-1 and block the apoptosome-mediated activation of caspase-9, which is an upstream event for caspase-3 activation (Beere et al, 2000;Saleh et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

et al. 2006

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The subfamily of WNK (with no K ¼ lysine) protein kinases has four human members and germline mutations in the WNK1 and WNK4 genes were recently found to cause pseudohypoaldosteronism type II, a familial hypertension disease. Here, we describe cloning and functional analysis of a further WNK member, human WNK3. Endogenous WNK3 protein is an active protein kinase when immunoprecipitated from cells and its overexpression increases the survival of HeLa cells by delaying the onset of apoptosis. Suppression of endogenous WNK3 protein by RNA interference accelerates the apoptotic response and promotes the activation of caspase-3. The mechanism of WNK3 action involves interaction with procaspase-3 and heat-shock protein 70. These results demonstrate a role for WNK3 in promoting cell survival and suggest a mechanism at the level of procaspase-3 activation.

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Section: Discussionmentioning

confidence: 99%

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

et al. 2006

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“…A number of studies have documented that HSP levels increase in the ischemic penumbra of the brain in animal models of focal ischemia, which is an area where many injured neurons survive [19] . It has been reported that gene transfer induced HSP70 overexpression protects neurons from ischemic brain damage in experimental rat stroke models [20] . Additionally, the overexpression of HSP70 inhibits the activation of NF-κB, which is persistently activated during ischemia and appears to promote apoptotic cell death [21] .…”

Section: Discussionmentioning

confidence: 99%

Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia

et al. 2011

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Aim: To examine the effects of a mixed formulation composed of prostaglandin E1 and lithium (PGE1+Li mixture) on brain damage after cerebral ischemia. The effects of the mixture on protein expression of heat shock proteins (HSPs), p53, and Bcl-2 were also determined. Methods: Brain ischemia was induced with a permanent middle cerebral artery occlusion (pMCAO) in rats. Rats were treated with a single intravenous administration of PGE1, lithium or a PGE1+Li mixture immediately after the ischemic insult. The infarct volume and motor behavior deficits were analyzed 24 h after the ischemic insult. The protein levels of HSP70, glucose-regulated protein 78 (GRP78), HSP60, Bcl-2, and p53 in the striatum of the ipsilateral hemisphere were examined using immunoblotting. Results: The mixture (PGE1 22.6 nmol/kg+Li 0.5 mmol/kg) reduced infarct volume and neurological deficits induced by focal cerebral ischemia. Moreover, the mixture had a greater neuroprotective effect against cerebral ischemia compared with PGE1 or lithium alone. The mixture was effective even if it was administered 3 h after ischemia. PGE1+Li also significantly upregulated cytoprotective HSP70, GRP78, HSP60, and Bcl-2 protein levels, while decreasing p53 expression. Conclusion: These results demonstrated a PGE1+Li mixture with a therapeutic window of up to 3 h for clinical treatment of cerebral ischemia. The PGE1+Li mixture potentially exerts a protective effect after stroke through the induction of HSPs and Bcl-2 proteins.

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“…54 Using in vitro systems, hsp70 was found to prevent apoptosome formation 55 and caspase 3 activation. 56 In these studies, however, participation of a DnaJ family member(s) was not given attention. Using in vitro systems, King et al 57 showed that the hsc70/dj1 chaperone pair bind to p53 and may regulate the stabilization and localization of p53.…”

Section: Hsp70/dnaj Chaperone Pair Prevents Chop-induced Apoptosis Thmentioning

confidence: 99%

hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria

et al. 2004

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We reported that the endoplasmic reticulum (ER) stress pathway involving CHOP, a member of the C/EBP transcription factor family, plays a key role in nitric oxide (NO)-mediated apoptosis of macrophages and pancreatic b cells. We also showed that the cytosolic chaperone pair of hsp70 and dj1 (hsp40/hdj-1) or dj2 (HSDJ/hdj-2) prevents NO-mediated apoptosis upstream of cytochrome c release from mitochondria. To analyze roles of the chaperone pair in preventing apoptosis, RAW 264.7 macrophages stably expressing hsp70 and dj1 or dj2 were established. The chaperone pair prevented LPS/IFN-c-induced and NO-mediated apoptosis downstream of CHOP induction. hsp70 mutant protein lacking the ATPase domain or the C-terminal EEVD sequence were not effective in preventing CHOP-induced apoptosis. A mutant dj2 lacking the C-terminal prenylation CaaX motif, was also not effective. When wild-type RAW 264.7 cells were treated with LPS/IFN-c, NOmediated apoptosis was induced, and proapoptotic Bcl-2 family protein Bax was translocated from cytosol to mitochondria. This translocation was prevented in cells stably expressing hsp70/dj2, and in CHOP knockout cells. Overexpression of CHOP in wild-type cells also induced translocation of Bax and this translocation was prevented in cells expressing hsp70/dj2. CHOP-induced apoptosis was prevented by Bax knock-down. Coimmunoprecipitation experiments showed that Bax interacts with both hsp70 and dj1/dj2. ATPase domain of hsp70 was necessary for the binding with Bax. These findings indicate that CHOP-induced apoptosis is mediated by translocation of Bax from the cytosol to the mitochondria, and hsp70/dj1 or dj2 chaperone pair prevents apoptosis by interacting with Bax and preventing translocation to the mitochondria.

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Heat Shock Protein 70 Inhibits Apoptosis Downstream of Cytochrome c Release and Upstream of Caspase-3 Activation

Cited by 431 publications

References 57 publications

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia

hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria

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