Effect of nitric oxide on endoplasmic reticulum calcium homeostasis, protein synthesis and energy metabolism

Doutheil, Jens; Althausen, Sonja; Treiman, Marek; Paschen, Wulf

doi:10.1054/ceca.1999.0099

Cited by 67 publications

(43 citation statements)

References 42 publications

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“…This suggested that protein folding capacity of P-cells is easily exhausted, and that hypothesized that NO perturbs ER function and leads to apoptosisthroughthe ERstress responsepathway. We(13) and others (37) found that NOincreases cytosolic Ca2+. Wefurther speculated that NOdisturbes ERCa2+ho-meostasis.Among agents whichincrease cytosolic Ca2+,only the agents depleting ER Ca2+can induce CHOPexpression and lead to apoptosis (13).…”

Section: Lessons From Akita Micementioning

confidence: 58%

Endoplasmic Reticulum Stress and Diabetes Mellitus.

2003

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Pancreatic p-cells are strongly engaged in protein secretion and have highly developed endoplasmic reticulum (ER). Proper folding of polypeptide into a threedimensional structure is essential for cellular function and protein malfolding can threaten cell survival.Various conditions can perturb the protein folding in the ER, which is collectively called ER stress. In order to adapt ERstress conditions, the cells respond in three distinct ways such as transcriptional induction of ER chaperones, translational attenuation, and ER-associated degradation (ERAD). However, when ER functions are severely impaired, the cell is eliminated by apoptosis via transcriptional induction of CHOP/GADD153, the activation of CJUNNH2-terminal kinase, and/or the activation of caspase-12. Recent studies have revealed that pcell is one of the most susceptible cells for ERstress, and ERstress-mediated apoptosis in p-cells can be a cause of diabetes. A comprehensive understanding of the impact of the ER stress pathway in p-cells and how it relates to the development of diabetes maycontribute to provide new targets for the prevention and treatment of this disease.

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Section: Lessons From Akita Micementioning

confidence: 58%

Endoplasmic Reticulum Stress and Diabetes Mellitus.

2003

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“…Moreover, exposing primary neuronal cell cultures to an NO-donor results in the inactivation of the ER Ca 2+ pump, depletion of ER Ca 2+ stores and a long-lasting suppression of protein synthesis (Doutheil et al, 2000). These studies suggest a crucial role for oxidative stress on ER functions.…”

Section: Journal Of Cell Science 121 (6)mentioning

confidence: 81%

The PKCδ -Abl complex communicates ER stress to the mitochondria – an essential step in subsequent apoptosis

Mochly‐Rosen

2008

Journal of Cell Science

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Conditions that compromise protein folding in the endoplasmic reticulum trigger the unfolded protein response (UPR), which either restores proper protein folding or results in cellular demise through apoptosis. In this study, we found that, in response to ER stress in vivo and in vitro, PKCδ translocates to the ER where it binds to the tyrosine kinase Abl. Tyrosine phosphorylation and kinase activity of PKCδ are required for PKCδ binding to Abl in the ER. Moreover, we found that inhibition of PKCδ by the PKCδ-specific peptide inhibitor δV1-1 or by silencing of PKCδ reduces ER-stress-induced JNK activation and inhibits ER-stress-mediated apoptosis. Furthermore, the inhibitor of PKCδ kinase activity rottlerin blocks the translocation of the PKCδ-Abl complex from the ER to the mitochondria and confers protection against apoptosis. Thus, PKCδ communicates ER stress to the mitochondria by binding to ER-localized Abl. The PKCδ-Abl complex then translocates to the mitochondria, communicating ER stress to this organelle, thereby, triggering apoptosis.

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“…Although we cannot completely rule out this mechanism, CRT, which is hyperexpressed in HCV core-expressing cells (Figure 2a and b), has been reported to inhibit the SERCA2b function (John et al, 1998) and lead to ER calcium depletion. Furthermore, inducible nitric oxide synthase (iNOS) production has been reported to be induced by HCV core (de Lucas et al, 2003) and inhibit SERCA2b activity (Doutheil et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion

et al. 2005

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Hepatitis C virus (HCV) core, known to be involved in liver carcinogenesis, is processed in the endoplasmic reticulum (ER). We thus investigated the impact of three HCV core isolates on ER stress, ER calcium signalling and apoptosis. We show that HCV core constructs trigger hyperexpression of Grp78/BiP, Grp 94, calreticulin and sarco/endoplasmic reticulum calcium ATPase, inducing ER stress. By using the ER-targeted aequorin calcium probe, we found that ER calcium depletion follows ER stress in core-expressing cells. HCV core induces apoptosis through overexpression of the CHOP/ GADD153 proapoptotic factor, Bax translocation to mitochondria, mitochondrial membrane depolarization, cytochrome c release, caspase-3 and PARP cleavage. Furthermore, reversion of HCV core-induced ER calcium depletion (by transfection of SERCA2) completely abolished mitochondrial membrane depolarization, suggesting that both ER stress (through CHOP overexpression) and calcium signalling play a major role in the HCV core-mediated control of apoptosis. ER stress and apoptosis were also found in a proportion of HCV-fulllength replicon-expressing cells and in the liver of HCV core transgenic mice. In conclusion, our data demonstrate that HCV core deregulates the control of apoptosis by inducing ER stress and ER calcium depletion providing new elements to understand the mechanisms involved in HCV-related liver chronic diseases.

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Effect of nitric oxide on endoplasmic reticulum calcium homeostasis, protein synthesis and energy metabolism

Cited by 67 publications

References 42 publications

Endoplasmic Reticulum Stress and Diabetes Mellitus.

Endoplasmic Reticulum Stress and Diabetes Mellitus.

The PKCδ -Abl complex communicates ER stress to the mitochondria – an essential step in subsequent apoptosis

Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion

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