Activation of the ER stress gene gadd153 by hepatitis C virus sensitizes cells to oxidant injury

Ciccaglione, Anna Rita; Marcantonio, Cinzia; Tritarelli, Elena; Equestre, Michele; Vendittelli, Francesca; Costantino, Angela; Geraci, Andrea; Rapicetta, Maria

doi:10.1016/j.virusres.2007.02.006

Cited by 32 publications

(28 citation statements)

References 59 publications

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“…Overexpression of GADD153 was reported to promote cell-cycle arrest and/or apoptosis, and deficiency of GADD153 could protect cells from ER stress-induced apoptosis, indicating that GADD153 plays an important role in the induction of ER stress-related apoptosis. 26,[29][30][31][32] Therefore, the elevation of CHOP/ GADD153 in this study not only indicates the activation of ER stress after RD, but also suggests the involvement of ER stress in retinal cell apoptosis.…”

Section: Discussionmentioning

confidence: 92%

“…They represent two different mechanisms during ER stress: GRP78 is involved in the unfolding protein reaction and the protection mechanism during ER stress; GADD153 is involved in injury mechanism induced by excessive ER stress. 11,12,25,26 The upregulation of the above two markers is an indication of ER stress. The aim of this study is to investigate the expression of the above two markers in RD model and its association with the apoptosis of retinal cells, in an attempt to discuss the involvement of ER stress-mediated apoptosis in post-RD visual impairment.…”

Section: Introductionmentioning

confidence: 99%

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Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication

Liu

Qian

Wang

et al. 2009

Eye

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Purpose To investigate the expression of endoplasmic reticulum (ER) stress-related genes, glucose-regulated protein 78 (GRP78) and growth arrest DNA damage-inducible gene 153 (GADD153)/CPEBP homologous protein (CHOP), in rat retinal detachment (RD) model. Materials and methods At various time points after RD, the apoptosis of retinal cells was detected by TdT-mediated fluorescein-16-dUTP nick-end labelling (TUNEL) assay; GRP78 and GADD153 mRNA levels were detected by reverse transcription (RT)-PCR; proteins were detected by western blotting analysis; protein distributions in the retinal cells were observed by immunofluorescence using laser-scanning confocal microscope. Results After RD, the apoptosis was peaked on 2-4 d and then dropped down. The GRP78 mRNA and GADD153 mRNA levels in RD groups on 0.5, 1, 2, and 4 d were all significantly higher than those in the control group (Po0.05). The expression of GRP78 mRNA peaked on 1-2 d after RD. Expression of GRP78 protein was significantly higher than that in the normal control group on 0.5, 1, 2, 4, 8, 16, and 32 d after RD (Po0.05). The expression of GRP78 protein was observed in all the layers of retina in the RD groups, and peaked on 8, 16, and 32 d. The expression of GADD153 protein, mostly in photoreceptor layers, was significantly higher than that in the control group on 0.5, 1, 2, and 4 d after RD (Po0.05). Conclusions ER stress-related markers, GRP78 and GADD153, are elevated after RD.The elevation of GADD153 is in parallel with the post-RD apoptosis of retinal cells, suggesting that ER stress-mediated death is likely to be activated after RD and involved in post-RD vision loss.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication

Liu

Qian

Wang

et al. 2009

Eye

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“…Normally, CHOP is expressed at low levels under nonstressed conditions. Overexpression of CHOP was found to activate apoptosis, and deficiency of CHOP can suppress caspase-12 expression and prevent ER stress-induced apoptosis, indicating that CHOP is important for initiating ER stress-related apoptosis [40,41]. In our experiments, the induction of CHOP mRNA after A2E treatment and blue light exposure was biphasic, with a first peak at 3 h and a second peak at 48 h. The initial increase in CHOP mRNA indicates a rapid response to ER stress and acute cellular damage which also has been reported to occur in a variety of cell types [42].…”

Section: Discussionmentioning

confidence: 99%

Expression of Endoplasmic Reticulum Stress Markers GRP78 and CHOP Induced by Oxidative Stress in Blue Light-Mediated Damage of A2E-Containing Retinal Pigment Epithelium Cells

Feng

Chen²,

Sun³

et al. 2014

Ophthalmic Res

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Aims: Age-related lipofuscin N-retinylidene-N-retinylethanolamine (A2E) accumulated in human retinal pigment epithelium (RPE) cells confers susceptibility to blue light-mediated damage, which represents one pathogenesis of age-related macular degeneration. This study investigated the expression of 2 best-characterized endoplasmic reticulum (ER) stress markers, glucose-related protein 78 (GRP78) and C/EBP homologous protein (CHOP), as well as their regulation by oxidative stress after blue light-mediated damage of A2E-containing RPE cells. Methods: ARPE-19 cells were incubated with A2E (10, 25, 50 μM) for 2 h and exposed to blue light for 20 min. A2E distributions in RPE cells were assessed via laser scanning confocal microscope and liquid chromatography-mass spectrometry. Cell viability was measured by a Cell Titer 96 Aqueous One Solution cell proliferation assay. The quantity of intracellular reactive oxygen species (ROS) was detected by dihydroethidium fluorescence using flow cytometry. Expressions of GRP78 and CHOP were measured at both mRNA and protein levels. To examine the role of oxidative stress in regulating GRP78 and CHOP expression, RPE cells were pretreated with the antioxidant N-acetylcysteine (NAC) for 2 h. RNA interference of GRP78 performed by short hairpin RNA was used to evaluate the effect of GRP78 in blue light-mediated damage of RPE cells. Results: After blue light exposure, A2E-treated RPE cells showed a gradual decrease in cell viability and a particular increase in ROS levels. Meanwhile, the expressions of GRP78 and CHOP in A2E-treated RPE cells were significantly increased at different time points after illumination. Pretreatment with NAC attenuated the expression of 2 ER stress markers, especially CHOP in A2E and blue light-treated RPE cells. Silencing of GRP78 by RNA interference upregulated CHOP and caspase-12 expression as well as aggravated the blue light-mediated damage of A2E-laden RPE cells. Conclusion: RPE cells exhibited ROS accumulation and subsequent elevation of GRP78 and CHOP expression after A2E and blue light-induced damage. The ROS scavenger NAC diminished ER stress protein expression, suggesting a connection between ER and oxidative stress in blue light-mediated damage of A2E-containing RPE cells. Besides, GRP78 may play a protective role in it.

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“…HCV protein expression and HCV RNA replication take place primarily in the ER or an ER-like membranous structure (39,46). Like other members of the family Flaviviridae, such as dengue virus (69), Japanese encephalitis virus (69), West Nile virus (41), and bovine viral diarrhea virus (26), HCV has been reported to induce ER stress in the host cells (5,14,17,55,60). ER stress is triggered by perturbations in normal ER function, such as the accumulation of unfolded or misfolded proteins in the lumen.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that HCV nonstructural proteins form the replication complex on the endoplasmic reticulum (ER) membrane (4,19,39,46). It was recently reported that HCV infection (55) as well as the transfection of the full-length HCV replicon (17) and the expression of the entire HCV polyprotein (14) induced an ER stress response. Therefore, we tested whether HCV infection in our system induces ER stress.…”

Section: Vol 82 2008 Hcv Induces Mitochondrion-mediated Apoptosis 1mentioning

confidence: 99%

Hepatitis C Virus Infection Induces Apoptosis through a Bax-Triggered, Mitochondrion-Mediated, Caspase 3-Dependent Pathway

Deng

Adachi

Kitayama

et al. 2008

J Virol

147

136

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We previously reported that cells harboring the hepatitis C virus (HCV) RNA replicon as well as those expressing HCV NS3/4A exhibited increased sensitivity to suboptimal doses of apoptotic stimuli to undergo mitochondrion-mediated apoptosis (Y. Nomura-Takigawa, et al., J. Gen. Virol. 87:1935Virol. 87: -1945Virol. 87: , 2006. Little is known, however, about whether or not HCV infection induces apoptosis of the virus-infected cells. In this study, by using the chimeric J6/JFH1 strain of HCV genotype 2a, we demonstrated that HCV infection induced cell death in Huh7.5 cells. The cell death was associated with activation of caspase 3, nuclear translocation of activated caspase 3, and cleavage of DNA repair enzyme poly(ADP-ribose) polymerase, which is known to be an important substrate for activated caspase 3. These results suggest that HCV-induced cell death is, in fact, apoptosis. Moreover, HCV infection activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change and its increased accumulation on mitochondrial membranes. Concomitantly, HCV infection induced disruption of mitochondrial transmembrane potential, followed by mitochondrial swelling and release of cytochrome c from mitochondria. HCV infection also caused oxidative stress via increased production of mitochondrial superoxide. On the other hand, HCV infection did not mediate increased expression of glucose-regulated protein 78 (GRP78) or GRP94, which are known as endoplasmic reticulum (ER) stress-induced proteins; this result suggests that ER stress is not primarily involved in HCV-induced apoptosis in our experimental system. Taken together, our present results suggest that HCV infection induces apoptosis of the host cell through a Bax-triggered, mitochondrion-mediated, caspase 3-dependent pathway(s).

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Activation of the ER stress gene gadd153 by hepatitis C virus sensitizes cells to oxidant injury

Cited by 32 publications

References 59 publications

Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication

Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication

Expression of Endoplasmic Reticulum Stress Markers GRP78 and CHOP Induced by Oxidative Stress in Blue Light-Mediated Damage of A2E-Containing Retinal Pigment Epithelium Cells

Hepatitis C Virus Infection Induces Apoptosis through a Bax-Triggered, Mitochondrion-Mediated, Caspase 3-Dependent Pathway

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