HSF1-Dependent Upregulation of Hsp70 by Sulfhydryl-Reactive Inducers of the KEAP1/NRF2/ARE Pathway

Zhang, Ying; Ahn, Young Hoon; Benjamin, Ivor J.; Honda, Tadashi; Hicks, Ronald J.; Calabrese, Vittorio; Cole, Philip A.; Dinkova‐Kostova, Albena T.

doi:10.1016/j.chembiol.2011.09.008

Cited by 99 publications

(114 citation statements)

References 23 publications

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“…Here, we observed that Aβ-depleted GSH, an indicator of oxidative stress, caused a mild increase in Hsp90 and Hsp70 levels. It is tempting to speculate that the mild increase of level of Hsps in Aβ-injected group may be due to previously described reactive oxygen species-induced dissociation and the activation of HSF-1 (Zhang et al 2011). GA pretreatment increased Hsp70 more significantly along with modulation of Hsp90 hippocampal level.…”

Section: Discussionmentioning

confidence: 99%

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

Zare

Motamedi

Digaleh

et al. 2015

Cell Stress and Chaperones

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One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of betaamyloid peptides (Aβ) in senile plaques. Aβ-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of Aβ (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aβ using passive avoidance (PA) task. As potential contributing factors in Aβ-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of Aβ-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aβ-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNELpositive cells as well. Thus, we conclude that GA exerts its protective effects against Aβ (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.

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Section: Discussionmentioning

confidence: 99%

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

Zare

Motamedi

Digaleh

et al. 2015

Cell Stress and Chaperones

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“…We have previously reported that TBE-31, at nanomolar concentrations, protects cells against peroxynitrite toxicity and showed the essential requirement for Nrf2 for protection (46). We next asked whether TBE-31 could protect cells with 6-TG in their genomic DNA against oxidative stress caused by UVA radiation.…”

Section: Resultsmentioning

confidence: 99%

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

Kalra

Knatko

Zhang

et al. 2012

Cancer Prevention Research

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Chronic treatment with azathioprine, a highly effective anti-inflammatory and immunosuppressive agent, profoundly increases the risk for development of unusually aggressive cutaneous squamous cell carcinoma. Its ultimate metabolite, 6-thioguanine (6-TG) nucleotide, is incorporated in DNA of skin cells, and upon exposure to UVA radiation, causes oxidative stress, followed by damage of DNA and associated proteins. The acetylenic tricyclic bis(cyano enone) TBE-31 is a strong inhibitor of inflammation and a potent inducer of the Keap1/Nrf2/ARE pathway, which orchestrates the expression of a large network of cytoprotective genes. We now report that long-term (five days per week for four weeks) topical daily applications of small (200 nmol) quantities of TBE-31 cause a robust systemic induction of the Keap1/Nrf2/ ARE pathway and decreases the 6-TG incorporation in DNA of skin, blood, and liver of azathioprine-treated mice, indicating extraordinary bioavailability and efficacy. In addition, TBE-31, at nanomolar concentrations, protects cells with 6-TG in their genomic DNA against oxidative stress caused by UVA radiation through induction of the Keap1/Nrf2/ARE pathway. At the same 6-TG DNA levels, Keap1-knockout cells, in which the pathway is constitutively upregulated, are highly resistant to UVA radiation-induced oxidative stress. The protective effects of both the Keap1-knockout genotype and TBE-31 are completely lost in the absence of transcription factor Nrf2. Our findings suggest that compounds of this kind are excellent candidates for mechanism-based chemoprotective agents against conditions in which oxidative stress and inflammation underlie disease pathogenesis. Moreover, their potential skin patch incorporation for transdermal delivery is an exciting possibility. Cancer Prev Res; 5(7); 973-81. Ó2012 AACR.

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“…The differential concentration dependence of the two responses suggests that activation of Nrf2 precedes that of Hsf1: The Keap1/Nrf2/ARE pathway is at the forefront of cellular defense, protecting against instant danger; the HSR closely follows to resolve subsequent potentially devastating damage, saving the proteome. This concept could have positive consequences for the treatment of renal inflammatory pathologies and related diseases (Zhang et al 2011). …”

Section: Hsp70/no Renal Cytoprotective Action As Consequence Of Statimentioning

confidence: 99%

Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy

Mazzei

Docherty

Manucha

2015

Cell Stress and Chaperones

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Urinary heat shock protein 70 (Hsp70) is rapidly increased in patients with clinical acute kidney injury, indicating that it constitutes a component of the endogenous stress response to renal injury. Moreover, experimental models have demonstrated that Hsp70 activation is associated with the cytoprotective actions of several drugs following obstruction, including nitric oxide (NO) donors, geranylgeranylacetone, vitamin D, and rosuvastatin. Discrete and synergistic effects of the biological activities of Hsp70 may explain its cytoprotective role in obstructive nephropathy. Basic studies point to a combination of effects including inhibition of apoptosis and inflammation, repair of damaged proteins, prevention of unfolded protein aggregation, targeting of damaged protein for degradation, and cytoskeletal stabilization as primary effectors of Hsp70 action. This review summarizes our understanding of how the biological actions of Hsp70 may affect renal cytoprotection in the context of obstructive injury. The potential of Hsp70 to be of central importance to the mechanism of action of various drugs that modify the genesis of experimental obstructive nephropathy is considered.

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HSF1-Dependent Upregulation of Hsp70 by Sulfhydryl-Reactive Inducers of the KEAP1/NRF2/ARE Pathway

Cited by 99 publications

References 23 publications

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy

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