PEDF: a multifaceted neurotrophic factor

Tombran-Tink, Joyce; Barnstable, Colin J.

doi:10.1038/nrn1176

Cited by 329 publications

(252 citation statements)

References 74 publications

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“…Although PEDF as a major endogenous angiogenic inhibitor has been extensively studied, the regulation of PEDF is not yet well understood (Tombran-Tink & Barnstable 2003b). Our study demonstrated that PEDF is secreted from RCEC and Mü ller cells.…”

Section: Discussionmentioning

confidence: 64%

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Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

226

152

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It has been shown that the balance between vascular endothelial growth factor (VEGF), a major angiogenic stimulator, and pigment epithelium-derived factor (PEDF), a potent angiogenic inhibitor, is critical for the regulation of vascular permeability and angiogenesis. However, the regulation of the balance is largely unclear. The present study demonstrated that there is a reciprocal interaction between VEGF and PEDF in the retina. PEDF significantly decreased VEGF expression in both retinal capillary endothelial cells (RCEC) and Mü ller cells. This PEDF effect was confirmed in the retina of rats with oxygen-induced retinopathy. Silencing of the PEDF gene by siRNA in Mü ller cells resulted in a significant upregulation of VEGF expression at both the RNA and protein levels, suggesting that PEDF is an endogenous negative regulator of VEGF. The further study of the mechanism showed that PEDF inhibited hypoxia-induced increases in VEGF promoter activity, HIF-1 nuclear translocation and mitogen activated protein kinase phosphorylation. These results suggest that PEDF inhibits VEGF expression at the transcriptional level. In addition, PEDF effectively inhibited VEGF binding to RCEC. Moreover, in vitro receptor-binding assay demonstrated that PEDF competed with VEGF for binding to VEGF receptor 2, which may represent a new mechanism for PEDF activity. On the other hand, VEGF significantly downregulated PEDF expression in RCEC, but not in retinal Mü ller cells, suggesting a VEGF receptormediated process. These results suggest that the reciprocal regulation between VEGF and PEDF may play a role in angiogenic control. The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes.

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Section: Discussionmentioning

confidence: 64%

“…PEDF is a multifaceted factor with neurotropic and anti-angiogenic functions (Tombran-Tink & Barnstable 2003b, Tombran-Tink et al 1991. Although PEDF as a major endogenous angiogenic inhibitor has been extensively studied, the regulation of PEDF is not yet well understood (Tombran-Tink & Barnstable 2003b).…”

Section: Discussionmentioning

confidence: 99%

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

226

152

View full text Add to dashboard Cite

show abstract

“…However, PEDF is not simply an antiangiogenic factor: it has neuroprotective effects in the nervous system and an apoptotic effect in endothelial cells. PEDF interacts with the NF-B pathway to stimulate the transcription of neuroprotective genes in the nervous system; and PEDF can generate anti-angiogenic and apoptosis signal by activating the Fas-Fas ligand (FasL) death cascade in endothelial and epithelial cells (34). Additionally, PEDF contributes as a natural angiogenesis inhibitor in two hormone-sensitive organs, the prostate and pancreas (35).…”

Section: Ncammentioning

confidence: 99%

Identification of aHoxc8-regulated transcriptional network in mouse embryo fibroblast cells

Lei

Juan

Kim

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor, Hoxc8, is a member of the homeobox gene family that is vital for growth and differentiation. Previously, we identified 34 genes whose expression levels were changed at least 2-fold by forced expression of Hoxc8 in C57BL͞6J mouse embryo fibroblast cells using a mouse 16,463-gene oligonucleotide microarray. In the present study, we used the combined power of microarray profiling, global Hoxc8 DNA-binding site analysis, and high-throughput chromatin immunoprecipitation assays to identify direct and biologically relevant targets of Hoxc8 in vivo. Here we show that 19 of the 34 responsive genes contain Hoxc8 consensus DNA-binding sequence(s) in their regulatory regions. Chromatin immunoprecipitation analysis indicated that Hoxc8-DNA interaction was detected in five of the 19 candidate genes. All of these five target genes have been implicated in oncogenesis, cell adhesion, proliferation, and apoptosis. Overall, the genes described here should aid in the understanding of global regulatory networks of Hox genes and to provide valuable insight into the molecular basis of Hoxc8 in development and carcinogenesis.cancer ͉ chromatin immunoprecipitation ͉ Hox protein binding sites ͉ microarray

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“…4 -10 Best studied as a potent inhibitor of angiogenesis, PEDF is a 46-kDa secretory protein with a serpin structure lacking protease inhibitory activity. [11][12][13][14] PEDF also binds with high affinity to matrix components, such as collagen I. 15 PEDF's inhibitory effect on mesenchymal cell proliferation in vitro was because of its ability to induce cell cycle arrest.…”

mentioning

confidence: 99%

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Schmitz

Protiva

Gattu

et al. 2011

The American Journal of Pathology

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Pigment epithelium-derived factor (PEDF) is important for maintaining the normal extracellular matrix. We hypothesized that the initiation of pancreatic fibrosis is dependent on the loss of PEDF. Pancreatic PEDF expression was assessed in wild-type mice fed either a control or ethanol diet using an intragastric feeding model. Pancreatitis responses were elicited with either a single episode or a repetitive ceruleininduced (50 g/kg, 6 hourly i.p. injections) protocol in wild-type and PEDF-null mice. Quantitative realtime PCR and immunoblotting were performed to assess fibrogenic responses. In wild-type animals, PEDF expression increased with pancreatitis and was more pronounced in mice fed ethanol. Compared with wild-type mice, ␣-smooth muscle actin staining and expression levels of fibrogenic markers (eg, transforming growth factor-␤1, platelet-derived growth factor, collagen I, and thrombospondin-1) were higher in PEDF-null mice at baseline. Sirius red staining revealed more fibrosis in PEDF-null versus wildtype pancreas 1 week after pancreatitis. Differences in tissue fibrosis resolved with longer recovery periods. PEDF overexpression suppressed thrombospondin-1 levels in vitro. Ethanol feeding and experimental pancreatitis increased PEDF expression in wildtype mice. PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wildtype mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in

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PEDF: a multifaceted neurotrophic factor

Cited by 329 publications

References 74 publications

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Identification of aHoxc8-regulated transcriptional network in mouse embryo fibroblast cells

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

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