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...
Angiogenesis has developed into a major area of cancer research. Recently, several newly identified signalling pathways have been shown to play a role in both normal and pathological (including tumour) angiogenesis. Several of the molecules involved in these pathways have potential as novel anti-cancer therapeutic targets including members of the ephrin/Eph receptor, Notch/delta, sprouty, hedgehog and roundabout/slit families. These developments are reviewed. Angiogenesis describes the formation of new blood vessels from the existing vasculature, a process that is relatively rare in the healthy human adult, occurring only during the female menstrual cycle and in wound healing. In contrast, angiogenesis occurs in many pathologies including diabetic retinopathy, arthritis, atherosclerosis, psoriasis and tumour growth. It has long been postulated that abrogation of angiogenesis could be an effective anticancer strategy; however, in order to be able to design effective antiangiogenic treatments, we must first understand how new blood vessels form. The inception of the vascular system occurs early in mammalian development with the differentiation and aggregation of angiogenic precursors in the embryo culminating in the blood islands of the visceral yolk sac. The early blood vessels of the embryo and yolk sac develop by aggregation of angioblasts that de novo create a primitive network of simple endothelial tubesthe process of vasculogenesis. Extensive research into the molecular mechanisms involved in vessel formation has identified proangiogenic factors such as vascular endothelial growth factor (VEGF) and the angiopoietins, together with antiangiogenic factors such as the thrombospondins and transcription factors leading to their expression like Id1 (reviewed in Bikfalvi and Bicknell, 2002). Two recent developments in the field have been the delineation of the mechanism by which hypoxia acts as a proangiogenic stimulus via the oxygen-sensing prolyl hydroxylase and hypoxia-inducible factor-a and the identification of several novel extracellular angiogenic signalling pathways. The latter include the ephrin/ Eph receptor, notch/delta, hedgehog, sprouty and slit/roundabout families (Figure 1). Here, we review the role of these signalling pathways in angiogenesis and point out where appropriate as to how they could be utilised to develop new anticancer strategies. EPHRINS, THE EPH TYROSINE KINASE RECEPTORS AND ANGIOGENESIS: VALIDATED ANTITUMOUR TARGETSThe ephrin ligands and Eph receptors comprise an increasingly studied family of signalling molecules originally identified some 13 years ago. Like other families of signalling molecules, they are not restricted to the endothelium, but are found in numerous cell types. Also, like the notch/delta family described later, the ephrin ligands and their Eph receptors are both membrane-bound molecules. The ephrin ligands are divided into A and B type molecules that are distinguished by the way in which they are anchored in the plasma membrane. Thus, the ephrin A ligands are tether...
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