Reticulon‐1C acts as a molecular switch between endoplasmic reticulum stress and genotoxic cell death pathway in human neuroblastoma cells

Sano, Federica Di; Fazi, Barbara; Tufi, Roberta; Nardacci, Roberta; Piacentini, Mauro

doi:10.1111/j.1471-4159.2007.04479.x

Cited by 38 publications

(71 citation statements)

References 32 publications

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“…We have previously observed that RTN-1C-overexpressing cells (that is SH-SY5Y RTN-1C treated with doxycycline) are relatively resistant against DNAdamaging agents such as etoposide or cisplatin, as compared to controls (SH-SY5Y Tet12 or SH-SY5Y RTN-1C cells cultured in tetracycline-free conditions). 23 In contrast, we found that the overexpression of RTN-1C had no effect on the propensity of cells to expose phosphatidylserine and to lose viability (Figure 2a Figure 3a, bottom panels). It should be noted that neither SH-SY5Y Tet12 nor SH-SY5Y RTN-1C cells did manifest any signs of apoptosis at these time points (Figure 2a and b), meaning that the MITO-induced ecto-CRT exposure is an early event.…”

Section: Resultsmentioning

confidence: 76%

“…[20][21][22] RTNs localize primarily to the ER membrane and possess unique N-terminal parts and a common 200-amino-acid C-terminal domain containing two long hydrophobic sequences that were suggested to form Ca 2 þ -permeable pores in the ER membrane. [23][24][25] RTN-1C represents the smallest variant of the reticulon 1 gene 26 and it is specifically expressed by neurons and cells of neuroendocrine tissue. 27 In our study, we used the previously developed tetracycline-inducible SH-SY5Y RTN-1C human neuroblastoma model 23 consisting of a SH-SY5Y cell line stably expressing tetracycline-inducible RTN-1C (SH-SY5Y RTN-1C ) and a control cell line expressing the regulator vector alone (SH-SY5Y Tet12 ) (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…[23][24][25] RTN-1C represents the smallest variant of the reticulon 1 gene 26 and it is specifically expressed by neurons and cells of neuroendocrine tissue. 27 In our study, we used the previously developed tetracycline-inducible SH-SY5Y RTN-1C human neuroblastoma model 23 consisting of a SH-SY5Y cell line stably expressing tetracycline-inducible RTN-1C (SH-SY5Y RTN-1C ) and a control cell line expressing the regulator vector alone (SH-SY5Y Tet12 ) (Figure 1a). After addition of doxycycline, a tetracycline derivative, SH-SY5Y RTN-1C cells overexpress RTN-1C within hours, reaching a peak around 6 h that remains constant for several days (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

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Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

et al. 2007

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Some chemotherapeutic agents can elicit apoptotic cancer cell death, thereby activating an anticancer immune response that influences therapeutic outcome. We previously reported that anthracyclins are particularly efficient in inducing immunogenic cell death, correlating with the pre-apoptotic exposure of calreticulin (CRT) on the plasma membrane surface of anthracyclintreated tumor cells. Here, we investigated the role of cellular Ca 2 þ homeostasis on CRT exposure. A neuroblastoma cell line (SH-SY5Y) failed to expose CRT in response to anthracyclin treatment. This defect in CRT exposure could be overcome by the overexpression of Reticulon-1C, a manipulation that led to a decrease in the Ca 2 þ concentration within the endoplasmic reticulum lumen. The combination of Reticulon-1C expression and anthracyclin treatment yielded more pronounced endoplasmic reticulum Ca 2 þ depletion than either of the two manipulations alone. Chelation of intracellular (and endoplasmic reticulum) Ca 2 þ , targeted expression of the ligand-binding domain of the IP 3 receptor and inhibition of the sarco-endoplasmic reticulum Ca 2 þ -ATPase pump reduced endoplasmic reticulum Ca 2 þ load and promoted pre-apoptotic CRT exposure on the cell surface, in SH-SY5Y and HeLa cells. These results provide evidence that endoplasmic reticulum Ca 2 þ levels control the exposure of CRT. In contrast to prior belief, apoptotic cell death can be immunogenic and hence elicits an active immune response against dying tumor cells. 1 This is therapeutically relevant because immune defects that compromise the response against apoptotic cells reduce the efficacy of anticancer chemotherapy, both in suitable animal models and in patients. 2 We found that anthracyclins and g-irradiation are particularly efficient in inducing immunogenic cell death, at least in mouse models. [3][4][5] The immunogenicity of cellular demise correlates with the exposure of calreticulin (CRT) on the plasma membrane (PM) surface of stressed tumor cells, a phenomenon that manifests before the cells acquire signs of apoptosis such as phosphatidylserine exposure. Inhibition of CRT exposure curtails the capacity of anthracyclin-treated or irradiated tumor cells to vaccinate against cancer and reduces the therapeutic efficacy of anthracyclins on tumors established in immunocompetent hosts. 3-5 Provision of recombinant CRT or drug-mediated enforcement of CRT exposure rendered per se nonimmunogenic chemotherapies (for instance with etoposide and mitomycin C) immunogenic and boosted their therapeutic efficacy. 5 These results suggest that CRT exposure is both necessary and sufficient to render conventional chemotherapies immunogenic.CRT is an abundant Ca 2 þ -binding chaperone that is mostly present in the endoplasmic reticulum (ER) lumen, although it can also be found in other subcellular localizations. 6,7 When present on the surface of damaged cells, it can serve as an 'eat-me' signal and hence facilitate the recognition and later engulfment of the dying cells by macrophages 8 or by dendrit...

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

et al. 2007

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“…In particular, their proapoptotic function as a novel regulator of ER stress-mediated cell death is well characterized [39]. However, the molecular mechanism by which the reticulon family members orchestrate different cellular responses is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, RTN1C-overexpressing neuroblastoma cells show a significant increase in their susceptibility to cell death upon ER stress induction [39]. Moreover, RTN1C overexpression induces per se apoptosis via ER stress induction characterized by a significant and toxic ER store calcium depletion [40].…”

Section: Reticulons In Cell Deathmentioning

confidence: 99%

The reticulons: Guardians of the structure and function of the endoplasmic reticulum

Sano

Bernardoni

Piacentini

2012

Experimental Cell Research

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The endoplasmic reticulum (ER) consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. The tubules are shaped by a specific class of curvature stabilizing proteins, the reticulons and DP1; however it is still unclear how the sheets are assembled. The ER is the cellular compartment responsible for secretory and membrane protein synthesis. The reducing conditions of ER lead to the intra/inter-chain formation of new disulphide bonds into polypeptides during protein folding assessed by enzymatic or spontaneous reactions. Moreover, ER represents the main intracellular calcium storage site and it plays an important role in calcium signaling that impacts many cellular processes. Accordingly, the maintenance of ER function represents an essential condition for the cell, and ER morphology constitutes an important prerogative of it. Furthermore, it is well known that ER undergoes prominent shape transitions during events such as cell division and differentiation. Thus, maintaining the correct ER structure is an essential feature for cellular physiology. Now, it is known that proper ER-associated proteins play a fundamental role in ER tubules formation. Among these ER-shaping proteins are the reticulons (RTN), which are acquiring a relevant position. In fact, beyond the structural role of reticulons, in very recent years new and deeper functional implications of these proteins are emerging in relation to their involvement in several cellular processes.

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Brief alcohol exposure alters transcription in astrocytes via the heat shock pathway

et al. 2013

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Astrocytes are critical for maintaining homeostasis in the central nervous system (CNS), and also participate in the genomic response of the brain to drugs of abuse, including alcohol. In this study, we investigated ethanol regulation of gene expression in astrocytes. A microarray screen revealed that a brief exposure of cortical astrocytes to ethanol increased the expression of a large number of genes. Among the alcohol-responsive genes (ARGs) are glial-specific immune response genes, as well as genes involved in the regulation of transcription, cell proliferation, and differentiation, and genes of the cytoskeleton and extracellular matrix. Genes involved in metabolism were also upregulated by alcohol exposure, including genes associated with oxidoreductase activity, insulin-like growth factor signaling, acetyl-CoA, and lipid metabolism. Previous microarray studies performed on ethanol-treated hepatocyte cultures and mouse liver tissue revealed the induction of almost identical classes of genes to those identified in our microarray experiments, suggesting that alcohol induces similar signaling mechanisms in the brain and liver. We found that acute ethanol exposure activated heat shock factor 1 (HSF1) in astrocytes, as demonstrated by the translocation of this transcription factor to the nucleus and the induction of a family of known HSF1-dependent genes, the heat shock proteins (Hsps). Transfection of a constitutively transcriptionally active Hsf1 construct into astrocytes induced many of the ARGs identified in our microarray study supporting the hypothesis that HSF1 transcriptional activity, as part of the heat shock cascade, may mediate the ethanol induction of these genes. These data indicate that acute ethanol exposure alters gene expression in astrocytes, in part via the activation of HSF1 and the heat shock cascade.

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Reticulon‐1C acts as a molecular switch between endoplasmic reticulum stress and genotoxic cell death pathway in human neuroblastoma cells

Cited by 38 publications

References 32 publications

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

The reticulons: Guardians of the structure and function of the endoplasmic reticulum

Brief alcohol exposure alters transcription in astrocytes via the heat shock pathway

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