Expression of the Endoplasmic Reticulum Oxidoreductase Ero1α in Gastro-Intestinal Cancer Reveals a Link Between Homocysteine and Oxidative Protein Folding

Battle, Danielle M.; Gunasekara, S.; Watson, Graeme; Ahmed, Eltayeb Mohamed; Saysell, Colin G.; Altaf, Naveed; Sanusi, Abayomi L.; Munipalle, P C; Scoones, David; Walker, Julie; Viswanath, Y. K. S.; Benham, Adam M.

doi:10.1089/ars.2012.4651

Cited by 15 publications

(13 citation statements)

References 61 publications

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“…Ero1α is recognized as a cancer‐associated oxidase because its expression is significantly elevated in many cancers such as breast (Kutomi et al , ), gastrointestinal (Battle et al , ), and pancreatic (Kukita et al , ) cancers. Moreover, Ero1α enhances the expression of major histocompatibility complex class I antigen (Kukita et al , ), vascular endothelial growth factor (Tanaka et al , ), and programmed death‐ligand 1 (Tanaka et al , ) via oxidative folding to promote tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we observe that p-Ero1a is present in both cell extracts and culture medium (Figs 2E and 3C and D), implying that secreted p-Ero1a with high activity also functions to regulate extracellular redox homeostasis. Ero1a is recognized as a cancer-associated oxidase because its expression is significantly elevated in many cancers such as breast (Kutomi et al, 2013), gastrointestinal (Battle et al, 2013), and pancreatic (Kukita et al, 2015) cancers. Moreover, Ero1a enhances the expression of major histocompatibility complex class I antigen (Kukita et al, 2015), vascular endothelial growth factor (Tanaka et al, 2016), and programmed death-ligand 1 (Tanaka et al, 2017) via oxidative folding to promote tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…Ero1α utilizes oxygen as the final electron acceptor for de novo disulfide bond formation and transfers disulfides to PDI, which directly catalyzes disulfide formation in reduced substrates (Mezghrani et al , ; Tu & Weissman, ; Sevier & Kaiser, ). Ero1α is upregulated under hypoxic conditions (May et al , ), highly expressed in many cancers (Battle et al , ; Kukita et al , ), and involved in calcium flux and cell apoptosis (Li et al , ; Chin et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

et al. 2018

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Family with sequence similarity 20C (Fam20C), the physiological Golgi casein kinase, phosphorylates numerous secreted proteins that are involved in a wide variety of biological processes. However, the role of Fam20C in regulating proteins in the endoplasmic reticulum (ER) lumen is largely unknown. Here, we report that Fam20C interacts with various luminal proteins and that its depletion results in a more reduced ER lumen. We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding. Notably, phosphorylation of Ero1α is induced under hypoxia, reductive stress, and secretion-demanding conditions such as mammalian lactation. Collectively, our findings open a door to uncover how oxidative protein folding is regulated by phosphorylation in the secretory pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

et al. 2018

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“…ERO1‐α (endoplasmic reticulum disulfide oxidase) is involved in formation of disulfide bonds which are required for the proper conformation and function of secreted proteins . ERO1‐α is found to be overexpressed in gastrointestinal cancer , and breast cancer . Gelsolin (GSN) regulates cell proliferation, invasion, apoptosis and migration .…”

Section: Resultsmentioning

confidence: 99%

Effect of purified fractions from cell culture supernate of high‐density pre‐B acute lymphoblastic leukemia cells (ALL3) on the growth of ALL3 cells at low density

2016

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The mechanisms underlying the aberrant growth and interactions between cells are not understood very well. The pre-B acute lymphoblastic leukemia cells directly obtained from an adult patient grow very poorly or don't grow at all at low density (LD), but grow better at high starting cell density (HD). We found that the LD ALL3 cells can be stimulated to grow in the presence of diffusible, soluble factors secreted by ALL3 cells themselves growing at high starting cell density. We then developed a biochemical purification procedure that allowed us to purify the factor(s) with stimulatory activity and analyzed them by nanoliquid chromatography-tandem mass spectrometry (nanoLC-MS/MS). Using nanoLC-MS/MS we have identified several proteins which were further processed using various bioinformatics tools. This resulted in 8 protein candidates which might be responsible for the growth activity on non-growing LD ALL3 cells and their involvement in the stimulatory activity are discussed.

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“…Despite these conclusive links between oxidative injury and GPx7 expression in vivo , it is important to emphasize that the actual source of peroxide that causes ROS accumulation in absence of GPx7 remains to be identified. A possible involvement of Ero1 α [ 112 ] remains to be experimentally verified.…”

Section: Organismal Roles Of Er Peroxidasesmentioning

confidence: 99%

Destroy and Exploit: Catalyzed Removal of Hydroperoxides from the Endoplasmic Reticulum

Ramming

Appenzeller-Herzog

2013

International Journal of Cell Biology

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Peroxidases are enzymes that reduce hydroperoxide substrates. In many cases, hydroperoxide reduction is coupled to the formation of a disulfide bond, which is transferred onto specific acceptor molecules, the so-called reducing substrates. As such, peroxidases control the spatiotemporal distribution of diffusible second messengers such as hydrogen peroxide (H2O2) and generate new disulfides. Members of two families of peroxidases, peroxiredoxins (Prxs) and glutathione peroxidases (GPxs), reside in different subcellular compartments or are secreted from cells. This review discusses the properties and physiological roles of PrxIV, GPx7, and GPx8 in the endoplasmic reticulum (ER) of higher eukaryotic cells where H2O2 and—possibly—lipid hydroperoxides are regularly produced. Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated. Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme. Nonetheless, in vitro and in vivo studies have demonstrated that individual peroxidases serve specific, nonoverlapping roles in ER physiology.

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Expression of the Endoplasmic Reticulum Oxidoreductase Ero1α in Gastro-Intestinal Cancer Reveals a Link Between Homocysteine and Oxidative Protein Folding

Cited by 15 publications

References 61 publications

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

Effect of purified fractions from cell culture supernate of high‐density pre‐B acute lymphoblastic leukemia cells (ALL3) on the growth of ALL3 cells at low density

Destroy and Exploit: Catalyzed Removal of Hydroperoxides from the Endoplasmic Reticulum

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