AEG3482 Is an Antiapoptotic Compound that Inhibits Jun Kinase Activity and Cell Death through Induced Expression of Heat Shock Protein 70

Salehi, Amir H.; Morris, Stephen; Ho, Wai-chi; Dickson, Kathleen M.; Doucet, Geneviève; Milutinovic, Snezana; Durkin, Jon P.; Gillard, John W.; Barker, Philip A.

doi:10.1016/j.chembiol.2005.11.012

Cited by 49 publications

(37 citation statements)

References 57 publications

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“…Apoptosis by Hsp70 shRNA was also induced in the absence of A/-N (King, 2007). Hsp70 is pluripotent, protecting cells against apoptosis at multiple levels, including JNK activity suppression (Salehi et al, 2006;Bienemann et al, 2008), Bax translocation (Stankiewicz et al, 2005), cyt c release (Creagh et al, 2000), apoptosome assembly (Beere et al, 2000;Saleh et al, 2000), and caspase activation (Mosser et al, 1997). JNK activation remained intact in Q97-expressing neurons, eliminating its suppression by Hsp70 as the reason for apoptosis inhibition.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

King¹,

Goemans²,

Hafiz³

et al. 2008

J. Neurosci.

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Proteins containing extended polyglutamine repeats cause at least nine neurodegenerative disorders, but the mechanisms of diseaserelated neuronal death remain uncertain. We show that sympathetic neurons containing cytoplasmic inclusions formed by 97 glutamines expressed within human huntingtin exon1-enhanced green fluorescent protein (Q97) undergo a protracted form of nonapoptotic death that is insensitive to Bax deletion or caspase inhibition but is characterized by mitochondrial dysfunction. By treating the neurons with combined cytosine arabinoside and NGF withdrawal, we demonstrate that Q97 confers a powerful resistance to apoptosis at multiple levels: despite normal proapoptotic signaling (elevation of P-ser15-p53 and BimEL), there is no increase of Puma mRNA or Bax activation, both necessary for apoptosis. Even restoration of Bax translocation with overexpressed Puma does not activate apoptosis. We demonstrate that this robust inhibition of apoptosis is caused by Q97-mediated accumulation of Hsp70, which occurs through inhibition of proteasomal activity. Thus, apoptosis is reinstated by short hairpin RNA-mediated knockdown of Hsp70. These findings explain the rarity of apoptotic death in Q97-expressing neurons. Given the proteasomal blockade, we test whether enhancing lysosomal-mediated degradation with rapamycin reduces Q97 accumulation. Rapamycin reduces the amount of nonpathological Q25 by 70% over 3 d, but Q97 accumulation is unaffected. Interestingly, Q47 inclusions form more slowly as a result of constitutive lysosomal degradation, but fasterforming Q97 inclusions escape lysosomal control. Thus, cytoplasmic Q97 inclusions are refractory to clearance by proteasomal and lysosomal systems, leading to a toxicity that dominates over neuroprotective Hsp70. Our findings may explain the rarity of apoptosis but the inevitable cell death associated with polyQ inclusion diseases.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

King¹,

Goemans²,

Hafiz³

et al. 2008

J. Neurosci.

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“…EGF (human, recombinant) and sorafenib were from Funakoshi (Tokyo, Japan) and American Chemicals Custom (San Diego, CA, USA), respectively. GA and 17-AAG were used at concentrations reported previously (Sano, 2001;Salehi et al, 2006;Clark et al, 2009). The concentrations of other reagents were also the same as those in previous reports (Taniguchi et al, 2007;Kurosawa et al, 2009;Tada et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…(ROS)-related stimuli and/or stress specifically at greater concentrations (from 10 nM to 10 μM), and showing neuroprotective effects at lower concentrations (nM order) (Sano, 2001;Lu et al, 2002Lu et al, , 2009Kim et al, 2003;Salehi et al, 2006;Clark et al, 2009). However, the precise mechanism(s) for the dual effects of Hsp90 inhibition on cell fate has not been established, and the effects of Hsp90 inhibitors on orthovanadate, Na 3 VO 4 , -induced cytotoxicity have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

et al. 2012

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“…7 shows that expression of full-length p75NTR or the p75ICD rescued the growth-arrest phenotype, but full-length p75NTR that was cleavage resistant did not. We and others have shown that massive overexpression of full-length p75NTR or the p75ICD induces caspase cleavage and cell death (Bhakar et al, 2003;Kenchappa et al, 2006;Salehi et al, 2006), but supplementary material Fig. S4 shows that the modest overexpression of p75NTR or p75ICD used in this paradigm has no effect on caspase activation.…”

Section: P75ntr Cleavage Promotes Ngf-induced Growth Arrest Of Pc12 Cmentioning

confidence: 99%

The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling

Ceni

Kommaddi

Thomas

et al. 2010

Journal of Cell Science

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The p75 neurotrophin receptor (p75NTR) potentiates Trk signaling, but the underlying mechanisms remain uncertain. Here, we examine the relationship between p75NTR cleavage and Trk signaling. We found that, in PC12 cells, nerve growth factor (NGF) induces rapid and robust α-secretase- and γ-secretase-dependent cleavage of p75NTR, releasing the resulting intracellular domain into the cytosol. Brain-derived neurotrophic factor similarly induces p75NTR cleavage in primary cerebellar granule neurons. p75NTR cleavage occurs by means of Trk-dependent activation of MEK-Erk signaling and induction of α-secretase activity, and is independent of ligand binding to p75NTR. Neurons and PC12 cells lacking p75NTR display defects in neurotrophin-dependent Akt activation. Normal Akt activation is rescued using full-length p75NTR or the p75 intracellular domain, but not cleavage-resistant p75NTR. We then demonstrate that NGF-dependent growth arrest of PC12 cells requires p75NTR cleavage and generation of the intracellular domain. We conclude that generation of the soluble p75NTR intracellular domain by Trk-induced cleavage plays a fundamental role in Trk-dependent signaling events.

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AEG3482 Is an Antiapoptotic Compound that Inhibits Jun Kinase Activity and Cell Death through Induced Expression of Heat Shock Protein 70

Cited by 49 publications

References 57 publications

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling

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