EndoPDI, a novel protein-disulfide isomerase-like protein that is preferentially expressed in endothelial cells acts as a stress survival factor.
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.
Sullivan
Dianne C
DC
Molecular Angiogenesis Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Huminiecki
Lucasz
L
Moore
John W
JW
Boyle
Joseph J
JJ
Poulsom
Richard
R
Creamer
Daniel
D
Barker
Jonathan
J
Bicknell
Roy
R
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D018076:DNA, Complementary; D042783:Endothelial Cells / Q000201:enzymology*; D004790:Enzyme Induction; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000473:pathology*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D016415:Sequence Alignment; D013879:Thioredoxins; D014018:Tissue Distribution
D018076:DNA, Complementary; D009363:Neoplasm Proteins; D013879:Thioredoxins; D019704:Protein Disulfide-Isomerases; C480743:TXNDC5 protein, human