Geldanamycin induces CHOP expression through a 4-(2-aminoethyl)-benzenesulfonyl fluoride-responsive serine protease

Hosoi, Toru; Hyoda, Kanae; Okuma, Yasunobu; Nomura, Yasuyuki; Ozawa, Koichiro

doi:10.1038/sj.cr.7310122

Cited by 8 publications

(5 citation statements)

References 10 publications

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“…Geldanamycin is a benzoquinone ansamycin which binds to and inhibits HSP90 activity [70,71]. Interestingly, Hendershot and co-workers [72] have found that geldanamycin upregulates the expression of ER chaperones and CHOP, and we have found that geldanamycin induces CHOP expression through a 4-(2-aminoethyl)-benzenesulfonyl fluoride-responsive serine protease [73]. Moreover, HSP90 associates with PERK and IRE1α, ER-resident transmembrane protein kinases [74].…”

Section: Er Stress and Cancermentioning

confidence: 85%

Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

2009

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Various stresses, which impair ER (endoplasmic reticulum) function, lead to an accumulation of unfolded or misfolded proteins. ER stress triggers many rescuer responses, including a UPR (unfolded protein response). Increasing evidence has suggested that ER stress is involved in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and cerebral ischaemic insults), cancer, obesity and diabetes. In the present review, we consider the importance of ER stress under pathological conditions in mammals. Furthermore, we discuss the therapeutic potential for treatment targeting ER stress.

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Section: Er Stress and Cancermentioning

confidence: 85%

Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

2009

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“…However, when the ER functions are severely impaired, apoptotic pathway would be activated. This apoptosis is mediated by a pro-apoptotic transcription factor, CHOP (Hosoi et al 2007). Release of TRAF2 is believed to be another biomarker for ER stress, which activates the pro-caspase-12, accumulating on the ER membrane.…”

Section: Discussionmentioning

confidence: 99%

Human Prion Protein Mutants with Deleted and Inserted Octarepeats Undergo Different Pathways to Trigger Cell Apoptosis

Wang

Shi

et al. 2010

J Mol Neurosci

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Octarepeats region sequence is one of the most important characteristics of PrP topology. To explore the mechanism of deleted and inserted octarepeats mutants PrP-caused apoptosis, wild-type PrP (PrP-PG5), and PrP with deleted octarepeats (PrP-PG0) and with four (PrP-PG9) and seven (PrP-PG12) extra octarepeats were transiently induced into SH-SY5Y cell. The results indicated PrP-PG9 and PrP-PG12 mainly retained in fraction of cytoplasm, while PrP-PG5 and PrP-PG0 presented both in cell membrane and cytoplasm. Cells expressing PrP-PG9 and PrP-PG12 were sensitive to endoplasmic reticulum (ER) stimuli, tunicamycin, and brefeldin A. ER-stress-related proteins, Grp94, XBP1, TRAF2, and CHOP, were significantly increased in cells expressing PrP-PG9 and PrP-PG12, while Grp78 increased markedly 12 h and pro-caspase-12 decreased sharply 20 h post-transfection. It indicates that expressions of PrP mutants with inserted octarepeats cause ER stress and lead to cell apoptosis lately. Meanwhile, cellular Cytochrome C increased and Bcl-2 decreased obviously in cells expressing PrP-PG0, indicating triggering a mitochondrial-related apoptosis. These data highlight that PrP mutants in region of octarepeats may undergo different pathways to trigger cell apoptosis, in which PrPs with inserted octarepeats via ER stress and PrP mutant without octarepeats via mitochondrial-related pathway.

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“…Geldanamycin is reported to induce ER stress by activating the UPR pathway that ultimately enhances the expression of chaperone proteins Grp78 and Chop [30]. Accordingly, we found that the Neuro-2a cells treated with 2ng geldanamycin showed a signi cant increase in the mRNA expression of UPR mediators Grp78 (Fig 2A ) and Chop (Fig 2B ), as compared to the control cells.…”

Section: Resultsmentioning

confidence: 67%

Secretome derived from mesenchymal stromal cells primed with neurotrophic factors rescues Neuro-2a cells from endoplasmic reticulum stress-mediated loss of neurogenesis.

Teli

Nachanekar

Kale

et al. 2022

Preprint

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Endoplasmic reticulum (ER) stress-mediated accumulation of misfolded protein is a plausible stimulus for the pathogenesis of neurodegenerative diseases (ND). Under physiological conditions, ER stress activates the unfolded protein response (UPR) that repairs the misfolded proteins. Hence, to develop a physiologically relevant in vitro model system, we exposed Neuro-2a cells to an ER stress inducer which significantly affected the neurite outgrowth parameters and expression of neuronal markers without causing cell death in them. Here, we demonstrate that ER stress triggers early apoptosis, inflammation, and stress kinase activation in Neuro-2a cells. We have previously reported the regenerative potential of mesenchymal stromal cells (MSCs)-derived secretome in reversing the oxidative stress-induced loss of neurogenesis. The aim of this study was to investigate whether priming of MSCs with neurotrophic factors would enhance their neuroprotective potential, for which we used two distinct approaches. In the first approach, the ER-stressed Neuro-2a cells were subjected to a single exposure of conditioned medium (CM) derived from both naïve (naïve CM) and primed MSCs (primed CM), while in the second approach, the ER-stressed cells were subjected to multiple exposures of both naïve and primed CM. We observed that exposure of ER stress-induced Neuro-2a cells to primed CM significantly restored the neurite outgrowth parameters along with the expression of neuronal markers and also suppressed the induction of early apoptosis, inflammation, and activation of stress kinases. These results clearly underscore the importance of priming the MSCs with neurotrophic factors for developing more effective therapeutic strategies to combat ND.

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Geldanamycin induces CHOP expression through a 4-(2-aminoethyl)-benzenesulfonyl fluoride-responsive serine protease

Cited by 8 publications

References 10 publications

Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

Human Prion Protein Mutants with Deleted and Inserted Octarepeats Undergo Different Pathways to Trigger Cell Apoptosis

Secretome derived from mesenchymal stromal cells primed with neurotrophic factors rescues Neuro-2a cells from endoplasmic reticulum stress-mediated loss of neurogenesis.

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