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J. Biol. Chem., Vol. 278, Issue 47, 47079-47088, November 21, 2003

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

Dianne C. Sullivan, Lucasz Huminiecki, John W. Moore, Joseph J. Boyle¶, Richard Poulsom||, Daniel Creamer**, Jonathan Barker, and Roy Bicknell

From the Molecular Angiogenesis Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom, the Molecular Evolution Laboratory, Department of Genetics, Trinity College Dublin, Dublin 2, Ireland, the ^¶Department of Histology, Imperial College Medical School, University of London, Hammersmith Hospital, London W12 ONN, United Kingdom, the ^||In Situ Hybridization Laboratory, Cancer Research UK, The London Research Institute, London WC2A 3PX, United Kingdom, the ^**School of Medicine and Dentistry, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom, and the St John's Institute of Dermatology, St Thomas's Hospital, King's College London, London SE1 7EH, United Kingdom

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.

Received for publication, July 25, 2003 , and in revised form, September 2, 2003.

^* This work was supported by funding from Henry Smith's Charity of London and Cancer Research UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 44-1865-222458; Fax: 44-1865-222431; E-mail: Roy.Bicknell{at}cancer.org.uk.

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