Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells

Elanchezhian, R.; Periyasamy, Palsamy; Madson, Christian J.; Mulhern, Michael L.; Lynch, David W.; Troia, A.; Usukura, Jiro; Shinohara, Toshimichi

doi:10.1038/cddis.2012.40

Cited by 44 publications

(61 citation statements)

References 35 publications

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“…This phenotype might be primed by the limited glucose conditions and hypoxia in the bone microenvironment. Indeed, low glucose under hypoxic conditions induces an unfolded protein response (42). The interactions observed in our model (see Fig.…”

Section: Discussionmentioning

confidence: 62%

A Transcriptome-proteome Integrated Network Identifies Endoplasmic Reticulum thiol oxidoreductase (ERp57) as a Hub that Mediates Bone Metastasis

Santana-Codina

Carretero

Sanz‐Pamplona

et al. 2013

Molecular & Cellular Proteomics

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Bone metastasis is the most common distant relapse in breast cancer. The identification of key proteins involved in the osteotropic phenotype would represent a major step toward the development of new prognostic markers and therapeutic improvements. The aim of this study was to characterize functional phenotypes that favor bone metastasis in human breast cancer. We used the human breast cancer cell line MDA-MB-231 and its osteotropic BO2 subclone to identify crucial proteins in bone metastatic growth. We identified 31 proteins, 15 underexpressed and 16 overexpressed, in BO2 cells compared with parental cells. We employed a network-modeling approach in which these 31 candidate proteins were prioritized with respect to their potential in metastasis formation, based on the topology of the protein-protein interaction network and differential expression. The protein-protein interaction network provided a framework to study the functional relationships between biological molecules by attributing functions to genes whose functions had not been characterized. The combination of expression profiles and protein interactions revealed an endoplasmic reticulum-thiol oxidoreductase, ERp57, function- Large-scale genomic analysis has provided a wealth of information on biologically relevant systems, and the ability to analyze this information is crucial to uncovering important biological relationships. In breast cancer, microarray gene expression analysis is a promising technique for providing consistent patterns of variation in bone metastasis gene expression; the most common metastasis (80%) in those women who progress to an advanced stage of disease (1-4). However, a large number of genes with many diverse functions are identified as prognostic markers, without revealing much about the underlying biological mechanism.Genes that enhance or suppress bone metastasis are associated with multiple cellular processes that normally occur during metastasis progression, including survival and proliferation in the bone marrow microenvironment, and modification of bone structure and function (1). Many genes in this group encode secretory or cell surface proteins involved in cell homing to bone, angiogenesis, invasion, and osteoclast recruitment (1, 2, 5). Moreover, emerging evidence from murine models suggests that tumor-specific endocrine factors systematically stimulate the quiescent bone marrow compartment (BM), resulting in a BM-derived tumor microenvironment From the ‡Biological Clues

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Section: Discussionmentioning

confidence: 62%

A Transcriptome-proteome Integrated Network Identifies Endoplasmic Reticulum thiol oxidoreductase (ERp57) as a Hub that Mediates Bone Metastasis

Santana-Codina

Carretero

Sanz‐Pamplona

et al. 2013

Molecular & Cellular Proteomics

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“…The UPR also senses the nutritional state of the cell. For example, the PERK pathway has been shown to be activated by glucose deprivation and under hypoxic conditions (Koumenis et al 2002;Elanchezhian et al 2012). Similarly, amino-acid limitation also leads to attenuation of protein synthesis by phosphorylation of EIF2a phosphorylation via GCN2 kinase (Zhang et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of unfolded protein response in recombinant CHO cells

Prashad

Mehra

2014

Cytotechnology

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Genes in the protein secretion pathway have been targeted to increase productivity of monoclonal antibodies in Chinese hamster ovary cells. The results have been highly variable depending on the cell type and the relative amount of recombinant and target proteins. This paper presents a comprehensive study encompassing major components of the protein processing pathway in the endoplasmic reticulum (ER) to elucidate its role in recombinant cells. mRNA profiles of all major ER chaperones and unfolded protein response (UPR) pathway genes are measured at a series of time points in a high-producing cell line under the dynamic environment of a batch culture. An initial increase in IgG heavy chain mRNA levels correlates with an increase in productivity. We observe a parallel increase in the expression levels of majority of chaperones. The chaperone levels continue to increase until the end of the batch culture. In contrast, calreticulin and ERO1-L alpha, two of the lowest expressed genes exhibit transient time profiles, with peak induction on day 3. In response to increased ER stress, both the GCN2/PKR-like ER kinase and inositol-requiring enzyme-1alpha (Ire1a) signalling branch of the UPR are upregulated. Interestingly, spliced X-Box binding protein 1 (XBP1s) transcription factor from Ire1a pathway is detected from the beginning of the batch culture. Comparison with the expression levels in a low producer, show much lower induction at the end of the exponential growth phase. Thus, the unfolded protein response strongly correlates with the magnitude and timing of stress in the course of the batch culture.

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“…The reverse transcribed RNA was analyzed by quantitative polymerase chain reaction using SsoFast™ EvaGreen ® Supermix (Bio-Rad). The primer sequences for Nrf2, Keap1, and β-actin as described by Elanchezhian et al (5) were used for mRNA detection. The primer sequences for Nrf2, Keap1, and β-actin were: Nrf2 sense, 5'-ACACGGTCCACAGCTCATC-3' and antisense, 5'-TGCCTCCAAAGTATGTCAATCA-3': Keap1 sense, 5'-GGGTCCCCTACAGCCAAG-3' and antisense, 5'-TGGGGTTCCAGAAGATAAGC-3'; and β-actin sense 5'-CCAACCGCGAGAAGATGA-3' and 5'-CCAGAGGCGTACAGGGATAG-3' antisense.…”

Section: Evaluation Of Protein Levels In Hlecsmentioning

confidence: 99%

“…The ciliary body and blood vessels of the iris supply glucose and oxygen (O 2 ) to the lens, where it is present in a hypoxic environment containing 0.5-2.3% O 2 (2)(3)(4). The level of O 2 is a very important factor in cataract, and various cataractogenic stressors such as hypoxia, hypoxic conditions along with a low glucose level (5) or high glucose level (6), homocysteine (7), and galactose (6) are found to induce stress in the endoplasmic reticulum (ER), thereby mediating the activation of the unfolded protein response (UPR) along with the production of reactive oxygen species (ROS), which is usually abnormally increased, and lens epithelial cell (LEC) death (3,8,9).…”

Section: Introductionmentioning

confidence: 99%

“…A study by Elanchezhian et al (5) demonstrated that ROS increased in LECs in the germinative zone that differentiate into cortical fiber cells, where new fiber cells are generated over old lens fiber cells. These lens fiber cells were suggested to contain less Nrf2-dependent antioxidant protection, and the changes result in crystallin aggregation and oxidation in the posterior and cortical regions.…”

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confidence: 99%

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Attenuation of oxygen fluctuation-induced endoplasmic reticulum stress in human lens epithelial cells

Zheng

Chen

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Cataractogenic stresses are associated with the induction of endoplasmic reticulum (ER) stress. However, little is known about oxygen (O 2 )-induced ER stress in the lens. Cataract research has focused on elevated levels of O 2 in lens epithelial cells (LECs). Excessive levels or a lack of O 2 are known to induce ER stress whereas chronic ER stress activates the unfolded protein response (UPR). The present study investigated the hypothesis that the fluctuation of O 2 levels induces a UPR, and may be controlled by maintaining human LECs (hLECs) in a specific concentration of O 2 . Human LECs were cultured in different atmospheric levels of O 2 . Hypoxic conditions were determined by the level of hypoxia-inducible factor (HIF)-1α. 2',7'-Dichlorodihydrofluorescein diacetate and ethidium homodimer-1 staining were conducted to detect reactive oxygen species (ROS) and cell death, respectively. Protein blot analyses were performed with antibodies specific to antioxidant and UPR-specific proteins. Reverse transcription-quantitatative polymerase chain reaction assays were performed to quantify the mRNA levels of activated NF-E2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1). The treatment of human LECs with 0 and 20% atmospheric O 2 activated Nrf2/Keap1. The LECs shifted to 1% atmospheric O 2 from 0, 4 or 20% for 24 h showed decreased levels of Keap1. By contrast, hLECs cultured in 1% atmospheric O 2 for 24 h and then shifted to 0, 4 or 20% O 2 exhibited a significant upregulation of Nrf2. These results suggest that oxidative stress proteins were not expressed in a 1% O 2 environment. The O 2 levels in the culture medium were equilibrated within 2 h in the cell culture plates. These results showed that an appropriate oxygen environment for the culture of LECs is ~1 % atmospheric O 2 . Either 0 or 20% of atmospheric O 2 activated the UPR and the Nrf2/Keap1-mediated antioxidant system in LECs and chronic exposure to O 2 fluctuation led to ROS production and cell death. This study revealed that O 2 fluctuation-induced UPR/ER stress could be prevented by maintaining the cells in a 1% O 2 environment.

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Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells

Cited by 44 publications

References 35 publications

A Transcriptome-proteome Integrated Network Identifies Endoplasmic Reticulum thiol oxidoreductase (ERp57) as a Hub that Mediates Bone Metastasis

A Transcriptome-proteome Integrated Network Identifies Endoplasmic Reticulum thiol oxidoreductase (ERp57) as a Hub that Mediates Bone Metastasis

Dynamics of unfolded protein response in recombinant CHO cells

Attenuation of oxygen fluctuation-induced endoplasmic reticulum stress in human lens epithelial cells

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