ATF4 links ER stress with reticulophagy in glioblastoma cells

Zielke, Svenja; Kardo, Simon; Zein, Laura; Mari, Muriel; Covarrubias‐Pinto, Adriana; Kinzler, Maximilian N.; Meyer, Nina; Stolz, Alexandra; Fulda, Simone; Reggiori, Fulvio; Kögel, Donat; Wijk, Sjoerd J. L. van

doi:10.1080/15548627.2020.1827780

Cited by 86 publications

(64 citation statements)

References 64 publications

(134 reference statements)

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“…3A and 3F), indicating that the exposure of AECIIs to 95 % oxygen increased the expression of CHOP, a major pro-apoptotic transcription factor induced by ER stress. PERK and ATF6 were ERS sensors, ATF4 were their downstream-activated proteins that activated CHOP expression according to the previously reported mechanism [21][22][23]. As shown in Fig.…”

Section: Effects Of Hyperoxia On Grp-78 Chop and Ers Sensors Expressionmentioning

confidence: 66%

The Function Role of Ubiquitin Proteasome Pathway in the ER Stress-induced AECII Apoptosis during Hyperoxia Exposure

Zhu

et al. 2021

Preprint

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Backgroud: Bronchopulmonary dysplasia (BPD) is a major cause of mortality and morbidity in premature infants, characterized by alveolar dysplasia and pulmonary microvascular remodeling. In the present study, we have investigated the functional roles of ubiquitin proteasome pathway (UPP) in BPD, and its relationship with endoplasmic reticulum stress (ER stress, ERS) mediated AECII apoptosis. Methods: A hyperoxia-induced BPD rat model was constructed and the pathologic changes of lung tissues were evaluated by Hematoxylin-Eosin staining. Cell apoptosis and protein expression were determined by TUNEL assay and Western blotting, respectively. Further reagent kit with specific fluorescent substrate was utilized to measure the activity of 20s proteasome. Meanwhile, AECII were cultured in vitro and exposed to hyperoxia. AECII apoptosis were measured by flow cytometry. In contrast, MG132 treatment was induced to explore ubiquitin proteasome pathway during hyperoxia exposure on AECII apoptosis and ERS sensors expression.Results: A significant increase in apoptosis and total ubiquitinated proteins expression were observed in BPD rats and AECII culture, and the change of UPP was associated with ERS. In order to confirm the role of UPP in AECII apoptosis of BPD, AECII cells were treated by MG132 with the concentration of 10 μmol/L under hyperoxia exposure. We found that the proteins expression of GRP-78, PERK, ATF4, ATF6 and CHOP, as well as AECII apoptosis were increased following MG132 treatment. Furthermore, the relatively up-regulated in the levels of total ubiquitinated proteins expression and 20S proteasome activity were correlated with increased ERS sensors expression. Conclusions: Our findings indicate that UPP may participate in the ERS-induced AECII apoptosis under hyperoxia condition.

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Section: Effects Of Hyperoxia On Grp-78 Chop and Ers Sensors Expressionmentioning

confidence: 66%

The Function Role of Ubiquitin Proteasome Pathway in the ER Stress-induced AECII Apoptosis during Hyperoxia Exposure

Zhu

et al. 2021

Preprint

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“…The development of drugs and therapeutic methods by targeting ER-phagy to treat related diseases is an emerging research field at present. For example, it has been reported that loperamide can induce the expression of Cyclic amp-dependent transcription factor ATF-4 (ATF4) in glioblastoma cells [ 138 ]. With the transcriptional activation by ATF4, FAM134B, and TEX264 expression is enhanced [ 138 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, it has been reported that loperamide can induce the expression of Cyclic amp-dependent transcription factor ATF-4 (ATF4) in glioblastoma cells [ 138 ]. With the transcriptional activation by ATF4, FAM134B, and TEX264 expression is enhanced [ 138 ]. Subsequently, excessive ER-phagy is induced and autophagic cell death of cancer cells is triggered [ 138 ].…”

Section: Discussionmentioning

confidence: 99%

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Advances in ER-Phagy and Its Diseases Relevance

Qian

Cui

2021

Cells

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As an important form of selective autophagy in cells, ER-phagy (endoplasmic reticulum-selective autophagy), the autophagic degradation of endoplasmic reticulum (ER), degrades ER membranes and proteins to maintain cellular homeostasis. The relationship between ER-phagy and human diseases, including neurodegenerative disorders, cancer, and other metabolic diseases has been unveiled by extensive research in recent years. Starting with the catabolic process of ER-phagy and key mediators in this pathway, this paper reviews the advances in the mechanism of ER-phagy and its diseases relevance. We hope to provide some enlightenment for further study on ER-phagy and the development of novel therapeutic strategies for related diseases.

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“…On the contrary, another study in GB cells demonstrated that ATF4 played a key role to induce autophagic cell death via reticulophagy (i.e. the selective degradation of the endoplasmic reticulum) in response to loperamide treatment and in this context activation of ATF4 was suggested to be beneficial for tumor therapy 38 . These studies highlight the ambiguous character of the ATF4 mediated stress response depending on the experimental context.…”

Section: Discussionmentioning

confidence: 99%

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

Lorenz

Sittig

Urban

et al. 2021

Sci Rep

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The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.

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ATF4 links ER stress with reticulophagy in glioblastoma cells

Cited by 86 publications

References 64 publications

The Function Role of Ubiquitin Proteasome Pathway in the ER Stress-induced AECII Apoptosis during Hyperoxia Exposure

The Function Role of Ubiquitin Proteasome Pathway in the ER Stress-induced AECII Apoptosis during Hyperoxia Exposure

Advances in ER-Phagy and Its Diseases Relevance

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

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