Identification of protein disulfide isomerase as an endothelial hypoxic stress protein

Graven, Krista K.; Molvar, Christopher; Roncarati, Jill S.; Klahn, Brian D.; Lowrey, Shawna; Farber, Harrison W.

doi:10.1152/ajplung.00359.2001

Cited by 40 publications

(29 citation statements)

References 54 publications

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“…36,37 Protein disulfide isomerase (PDI), which is necessary for disulfide bond formation and, hence, protein folding, is also induced maximally in anoxia. 38 In addition, the endoplasmic reticulum resident kinase PERK has been shown recently to become hyperphosphorylated under hypoxia and anoxia, independent of HIF-1␣, leading to the phosphorylation of eIF2␣, which then results in hypoxia-induced translational attenuation 39 of most mRNAs. Moreover, the PERK-dependent translational attenuation pathway was shown to selectively increase the translation of ATF-4 mRNA during ER stress, 40 and this ER-generated signal may mediate an adaptive cellular response to hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Anoxic induction of ATF-4 through HIF-1–independent pathways of protein stabilization in human cancer cells

Ameri

Lewis

Raida

et al. 2004

Blood

161

121

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Section: Discussionmentioning

confidence: 99%

Anoxic induction of ATF-4 through HIF-1–independent pathways of protein stabilization in human cancer cells

Ameri

Lewis

Raida

et al. 2004

Blood

161

121

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“…There are a unique set of proteins found to be expressed in endothelial cells during hypoxia (37) and it is conceivable that EndoPDI might be essential for the folding and export of these additional proteins required for survival under hypoxia. Archetypal PDI is also up-regulated during hypoxia in endothelial cells (38) as well as in glial cells (21). The up-regulation of PDI in glial cells was shown to have a protective effect against hypoxic cell death in these cells (21).…”

Section: The Effect Of Lack Of Endopdi and Pdi Expression On The Secrmentioning

confidence: 97%

EndoPDI, a Novel Protein-disulfide Isomerase-like Protein That Is Preferentially Expressed in Endothelial Cells Acts as a Stress Survival Factor

Sullivan

Huminiecki

Moore

et al. 2003

Journal of Biological Chemistry

160

141

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We have identified a novel protein-disulfide isomerase and named it endothelial protein-disulfide isomerase (EndoPDI) because of its high expression in endothelial cells. Isolation of the full-length cDNA showed EndoPDI to be a 48 kDa protein that has three APWCGHC thioredoxin motifs in contrast to the two present in archetypal PDI. Ribonuclease protection and Western analysis has shown that hypoxia induces EndoPDI mRNA and protein expression. In situ hybridization analysis showed that EndoPDI expression is rare in normal tissues, except for keratinocytes of the hair bulb and syncytiotrophoblasts of the placenta, but was present in the endothelium of tumors and in other hypoxic lesions such as atherosclerotic plaques. We have compared the function of EndoPDI to that of PDI in endothelial cells using specific siRNA. PDI was shown to have a protective effect on endothelial cells under both normoxia and hypoxia. In contrast, EndoPDI has a protective effect only in endothelial cells exposed to hypoxia. The loss of EndoPDI expression under hypoxia caused a significant decrease in the secretion of adrenomedullin, endothelin-1, and CD105; molecules that protect endothelial cells from hypoxia-initiated apoptosis. The identification of an endothelial PDI further extends this increasing multigene family and EndoPDI, unlike archetypal PDI, may be a molecule with which to target tumor endothelium.Protein-disulfide isomerase (PDI) 1 is a ubiquitously expressed multifunctional protein found in the endoplasmic reticulum (ER). It constitutes around 0.8% of total cellular protein and can reach near millimolar concentrations in the ER lumen of some tissues. PDI plays a role in protein folding because of its ability to catalyze the formation of native disulfide bonds and disulfide bond rearrangement (1). Proteins targeted for secretion by the cell are inserted into and translocated across the ER membrane and enter the ER lumen in an unfolded state. PDI, together with a variety of other folding factors and molecular chaperones resident in the ER correctly fold the proteins ready for secretion (2). The accumulation of misfolded proteins in the ER, known as the Unfolded Protein Response, results in increased transcription of chaperones and folding catalysts. Proteins that fail to fold correctly are relocated to the cytosol for proteasomal degradation.PDI is a modular protein consisting of a, b, bЈ, aЈ, and c domains (3). The a and aЈ domains show sequence and structural homology to thioredoxin (Trx) and both contain the active site WCGHCK motif, constituting two independent catalytic sites for thiol-disulfide bond exchange reactions (4 -7). A ratelimiting step in the folding of many newly synthesized proteins is the formation of disulfide bridges (1) and the presence of WCGHCK in PDI is essential for this process, as confirmed by the loss of PDI activity following mutation of the cysteine residues within these motifs (5, 8). The b and bЈ domains also have the thioredoxin structural fold but lack the active site motif. Thus, PDI conta...

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“…This is an important question to address because of the crucial antithrombotic role played by healthy endothelium. PDI is present inside endothelial cells and is up-regulated under conditions of hypoxia [14][15][16]. Endothelial cells in culture also express PDI on their exofacial surface, and this PDI regulates the adhesive properties of both thrombospondin [17] and of its binding partner integrin αV β3 [18].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

Smith

Shah²,

Kamaludin

et al. 2015

Thrombosis Research

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Introduction: Cell surface thiol isomerase enzymes, principally protein disulphide isomerase (PDI), have emerged as important regulators of platelet function and tissue factor activation via their action on allosteric disulphide bonds. Allosteric disulphides are present in other haemostasis-related proteins, and we have therefore investigated whether thiol isomerase inhibition has any influence on two endothelial activities relevant to haemostatic regulation, namely activation of protein C and activation of plasminogen, with subsequent fibrinolysis.

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Identification of protein disulfide isomerase as an endothelial hypoxic stress protein

Cited by 40 publications

References 54 publications

Anoxic induction of ATF-4 through HIF-1–independent pathways of protein stabilization in human cancer cells

Anoxic induction of ATF-4 through HIF-1–independent pathways of protein stabilization in human cancer cells

EndoPDI, a Novel Protein-disulfide Isomerase-like Protein That Is Preferentially Expressed in Endothelial Cells Acts as a Stress Survival Factor

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

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