Two phases of disulfide bond formation have differing requirements for oxygen

Koritzinsky, Marianne; Levitin, Fiana; Beucken, Twan van den; Rumantir, Ryan Allister; Harding, Nicholas J.; Chu, Kenneth C.; Boutros, Paul C.; Braakman, Ineke; Wouters, Bradly G.

doi:10.1083/jcb.201307185

Cited by 123 publications

(99 citation statements)

References 72 publications

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“…The UPR is activated during hypoxia as a consequence of increased misfolded or unfolded proteins [8]. The UPR constitutes of three parallel signaling cascades initiated by PERK (PKR-like ER kinase), IRE1 (inositol-requiring protein 1) and ATF6 (activating transcription factor 6).…”

Section: Introductionmentioning

confidence: 99%

“…Other HIF-1 transcriptional targets are carbonic anhydrase 9 (CA9) and Glucose Transporter 1 (GLUT1). These proteins are respectively involved in deacidification and increased glucose uptake during hypoxia [7].The UPR is activated during hypoxia as a consequence of increased misfolded or unfolded proteins [8]. The UPR constitutes of three parallel signaling cascades initiated by PERK (PKR-like ER kinase), IRE1 (inositol-requiring protein 1) and ATF6 (activating transcription factor 6).…”

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confidence: 99%

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GABARAPL1 is required for increased EGFR membrane expression during hypoxia

Keulers

Schaaf

Peeters

et al. 2015

Radiotherapy and Oncology

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

GABARAPL1 is required for increased EGFR membrane expression during hypoxia

Keulers

Schaaf

Peeters

et al. 2015

Radiotherapy and Oncology

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“…This can be explained by the fact that, although total FGFR1 levels are restored, the mature form of the receptor is significantly underrepresented. This is not surprising, as although GSK2606414 relieves the inhibition of translation, hypoxia would still inhibit protein folding and maturation in the ER and Golgi (Koritzinsky et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Gestational stress induces the unfolded protein response, resulting in heart defects

Moreau

Shi

O׳Reilly

et al. 2017

Mechanisms of Development

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Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.

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“…Severe hypoxia (<5-10mm Hg) impacts other enzymatic oxygen-dependent processes such as the oxidative folding of proteins in the endoplasmic reticulum (ER) that are in transit en route to the extracellular space 34 . Accumulation of unfolded or misfolded proteins in the ER activates the unfolded protein response (UPR), where three sensors of ER stress (PERK, IRE1 and ATF6) regulate transcription and translation to increase folding capacity and protect against cell death [35][36][37] .…”

Section: Adaptationmentioning

confidence: 99%