Activating Transcription Factor 4 (ATF4)-ATF3-C/EBP Homologous Protein (CHOP) Cascade Shows an Essential Role in the ER Stress-Induced Sensitization of Tetrachlorobenzoquinone-Challenged PC12 Cells to ROS-Mediated Apoptosis via Death Receptor 5 (DR5) Signaling

Liu, Zixuan; Shi, Qiong; Song, Xiufang; Wang, Yuxin; Wang, Yawen; Song, Erqun; Song, Yang

doi:10.1021/acs.chemrestox.6b00181

Cited by 49 publications

(40 citation statements)

References 33 publications

(51 reference statements)

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“…With the highest score, an unidentified gene FP236383.10 with a prediction of being a miRNA in the databases, decreased the most, which remains for further investigation. All other genes were remarkably up-regulated for their transcription, among which the proteins of osgin1 [31], [32], hmox1 [33], [34], atf3 [35], [36], spns2 [37], ppp1r15a [38] and tiparp [39] possess certain degree of relationship with redox homeostasis, suggesting that the change of RPL10 is closely associated with redox homeostasis in the cells. To verify such a relationship, two typical proteins involved in redox homeostasis, OSGIN1 and HMOX1, were chosen for experimental verification.…”

Section: Resultsmentioning

confidence: 99%

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

et al. 2018

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Tumorigenesis is commonly known as a complicated process, in which reactive oxygen species (ROS) plays a critical role to involve in signal transduction, metabolism, cell proliferation and differentiation. Previously, ribosomal protein L10 (RPL10) was suggested to possess extra-ribosomal functions in pancreatic cancer cells in addition to being proposed as a tumor suppressor or transcription co-regulator. To better understand the relationship between RPL10 and tumorigenic potential in pancreatic cancer cells, chromatin immunoprecipitation sequencing reveals that RPL10 is unlikely to be a transcription factor without a specific binding motif for gene transcription. Additionally, transcriptome analysis indicates that RPL10 could regulate the expression of proteins related to ROS production. Moreover, RPL10 in mitochondria is closely associated with the regulation of ROS level by affecting Complex I activity and the subsequent events. Together, the present study suggests that the regulation of ROS level by mitochondrial RPL10 is one of the major extra-ribosomal functions in pancreatic cancer cells, which could be used as an indicator for the tumorigenesis of pancreatic cancer.

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Section: Resultsmentioning

confidence: 99%

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

et al. 2018

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“…Studies have demonstrated that ER stress increases the transcription of the gene encoding DR5 through activation of transcription factors ATF4 and CHOP (Chen, Hu et al, 2016, Liu, Shi et al, 2016. Therefore, we examined whether tcyDTDO activates a previously described (Cheong et al, 2011) DR5 transcriptional reporter construct.…”

Section: Ddas Upregulate Dr5 Through Both Transcriptional and Posttramentioning

confidence: 96%

Mechanistic Elucidation of the Antitumor Properties of a Novel Death Receptor 5 Activator

Wang

Law

Davis

et al. 2019

Preprint

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Disulfide bond Disrupting Agents (DDAs) are a new chemical class of agents recently shown to have activity against breast tumors in animal models. However, it is unknown how DDAs trigger cancer cell death without affecting nontransformed cells. As demonstrated here, DDAs are the first compounds identified that upregulate the TRAIL receptor DR5 through both transcriptional and posttranscriptional mechanisms. At the protein level, DDAs alter DR5 disulfide bonding to increase steady-state DR5 levels and oligomerization, leading to downstream Caspase 8 and 3 activation. DDAs and TRAIL synergize to kill cancer cells and are cytotoxic to HER2+ cancer cells with acquired resistance to the EGFR/HER2 tyrosine kinase inhibitor. Investigation of the mechanisms responsible for DDA selectivity for cancer cells reveals that DDA-induced upregulation of DR5 is enhanced in the context of EGFR overexpression, and DDA-induced cytotoxicity is strongly amplified by MYC overexpression. Together, the results demonstrate selective DDA lethality against oncogene-transformed cells, DDA-mediated DR5 upregulation and protein stabilization, and DDAs against drug-resistant and metastatic cancer cells. DDAs thus represent a new therapeutic approach to cancer therapy.

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“…ATF3 and ATF4 belong to the ATF/cAMP response element binding (ATF/CREB) family of transcription factors. 21,62 Members of the ATF/CREB family sense environmental stimulation signals and participate in cellular processes. Liu reported that the UPR increases ATF3 expression via p-eIF2-ATF4 signaling.…”

Section: Dovepressmentioning

confidence: 99%

“…It was previously reported that ATF3 played an integral part in the PERK/eIF2 signaling branch of the UPR. 21 PERK/ eIF2 cascade has been proved to be a remarkable pathway that could influence apoptosis. 22 For the past few years, multiple researchers have reported a potential correlation in ATF4/ATF3/CHOP.…”

Section: Introductionmentioning

confidence: 99%

<p>KLF6 Induces Apoptosis in Human Lens Epithelial Cells Through the ATF4-ATF3-CHOP Axis</p>

Tian¹,

Zhao²,

Bu³

et al. 2020

DDDT

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Background: Many studies have confirmed that high myopia is related to the high prevalence of cataracts, which results from apoptosis of lens epithelial cells (LECs) due to endoplasmic reticulum stress. Krüppel-like factor 6 (KLF6) is a tumor suppressor that is involved in the regulation of cell proliferation and apoptosis. Purpose: In this study, our purpose was to find the relationship between KLF6-induced apoptosis in LECs and ATF4 (activating transcription factor 4)-ATF3 (activating transcription factor 3)-CHOP (C/EBP homologous protein) signaling pathway. Methods: KLF6, ATF4, ATF3, and CHOP were ectopically expressed using cDNAs subcloned into the pCDNA3.1+ vector. ATF4, ATF3, and CHOP knockdown were performed by small interfering RNA (siRNA). Expression of relative gene was tested using QT-PCR and western-blot. Then, accompanied by UVB stimulation, cell viability was measured by CCK-8 assay; The cell damage was examined by live & dead staining; The apoptotic markers Bax and Bcl-2 were detected by immunoblotting; Quantitative apoptotic levels were measured with the Apoptosis Detection Kit; The expression level of reactive oxygen-free radical (ROS) was analyzed by DCFH-DA`probe. Results: Ectopically expressed ATF4, ATF3, and CHOP-induced apoptosis in cells, whereas ATF4, ATF3, and CHOP knockdown by small interfering RNA (siRNA) blocked KLF6induced apoptosis. In addition, we determined that ATF4 regulates ATF3 and CHOP expression and that ATF3 silencing reduces CHOP upregulation without changing ATF4 levels; however, ATF4 and ATF3 expression was unaffected by blockade of CHOP, suggesting that KLF6 triggers endoplasmic reticulum stress in LECs by mediating the ATF4-ATF3/CHOP axis. Besides, KLF6 overexpression significantly induced LEC apoptosis under UV radiation, as demonstrated by the elevated Bax/Bcl-2 ratio. Conclusion: The ATF4-ATF3-CHOP pathway plays an important role in KLF6-induced apoptosis in HLECs. Our results increase our understanding of the mechanisms that regulate LEC apoptosis and contribute to the development of a new preventative strategy for cataract.

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Activating Transcription Factor 4 (ATF4)-ATF3-C/EBP Homologous Protein (CHOP) Cascade Shows an Essential Role in the ER Stress-Induced Sensitization of Tetrachlorobenzoquinone-Challenged PC12 Cells to ROS-Mediated Apoptosis via Death Receptor 5 (DR5) Signaling

Cited by 49 publications

References 33 publications

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

Mechanistic Elucidation of the Antitumor Properties of a Novel Death Receptor 5 Activator

<p>KLF6 Induces Apoptosis in Human Lens Epithelial Cells Through the ATF4-ATF3-CHOP Axis</p>

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