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The transcriptional corepressor NAB2 blocks Egr-1-mediated growth factor activation and angiogenesis
P Houston1, C J Campbell, J Svaren
1Cardiovascular Systems Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, England. pb6174@glaxowellcome.co.uk
Abstract:
Effective tissue repair results from a rapid, temporally orchestrated series of events. At the site of local tissue injury, the production of many growth factors and cytokines is, in part, stimulated by the early growth response transcription factors such as Egr-1. Egr-1 protein binds to a family of corepressor proteins called NAB which function to block or limit Egr-1 trans-activation of cognate target genes. NAB2 blocks Egr-1 activation of the tissue factor (TF) promoter, Egr-1 stimulated production of PDGF-AB, HGF, TGFbeta(1), and VEGF and the endogenous expression of PDGF-AB and TGFbeta(1). Expression of a wild-type NAB2 but not a dominant negative NAB2 mutant abrogates Egr-1 driven TF promoter activity and tubule formation in an in vitro model of angiogenesis. These findings may have importance in any tissue that is subject to scarring after acute or chronic injury.
Insights
The corepressor NAB2 limits the activity of transcription factor Egr-1, crucial for tissue repair. Understanding this interaction is key to controlling scarring after injury.
Area of Science:
- Molecular biology
- Cellular biology
- Wound healing research
Background:
- Tissue repair involves a complex cascade of cellular events.
- Early growth response transcription factors, like Egr-1, are critical in initiating repair by stimulating growth factor production.
- Corepressor proteins of the NAB (Nervous system, Astrocytes, Brain) family regulate Egr-1 activity.
Purpose of the Study:
- To investigate the role of NAB2 as a corepressor of Egr-1 in the context of tissue repair.
- To determine how NAB2 modulates Egr-1's transcriptional activity on target genes involved in healing and scarring.
- To assess the impact of NAB2 on angiogenesis in an in vitro model.
Main Methods:
- Studied the interaction between Egr-1 and NAB2.
- Analyzed NAB2's effect on Egr-1-driven gene expression, including tissue factor (TF), PDGF-AB, HGF, TGFbeta(1), and VEGF.
- Utilized an in vitro angiogenesis model to evaluate the functional consequences of NAB2 expression on tubule formation.
Main Results:
- NAB2 was shown to block Egr-1's activation of the TF promoter.
- NAB2 inhibited Egr-1-stimulated production of PDGF-AB, HGF, TGFbeta(1), and VEGF.
- NAB2 also affected the endogenous expression of PDGF-AB and TGFbeta(1).
- Expression of wild-type NAB2, but not a dominant-negative mutant, abrogated Egr-1-driven TF promoter activity and in vitro tubule formation.
Conclusions:
- NAB2 acts as a critical negative regulator of Egr-1 activity in tissue repair pathways.
- NAB2's modulation of Egr-1 target genes, including those involved in angiogenesis and growth factor production, has implications for controlling scar formation.
- These findings highlight potential therapeutic targets for managing scarring in acute or chronic tissue injury.