Abstract
Pathological angiogenesis is a hallmark of many diseases. We demonstrated that TR3/Nur77 is an excellent target for pro-angiogenesis and anti-angiogenesis therapies. Here, we report that TR3 transcriptionally regulates endothelial cell migration, permeability and the formation of actin stress fibers that is independent of RhoA GTPase. 1) Amino acid residues 344-GRR-346 and de-phosphorylation of amino acid residue serine 351 in the DNA binding domain, and 2) phosphorylation of amino acid residues in the 41-61 amino acid fragment of the transactivation domain, of TR3 are required for its induction of the formation of actin stress fibers, cell proliferation, migration and permeability. The 41-61 amino acid fragment contains one of the three potential protein interaction motifs in the transactivation domain of TR3, predicted by computational modeling and analysis. These studies further our understanding of the molecular mechanism, by which TR3 regulates angiogenesis, identify novel therapeutic targeted sites of TR3, and set the foundation for the development of high-throughput screening assays to identify compounds targeting TR3/Nur77 for pro-angiogenesis and anti-angiogenesis therapies.
Highlights
Pathological angiogenesis is a hallmark of many diseases including cancer, inflammation, wound healing and ischemic heart disease
We further examined whether expression of TR3 is required for the induction of actin stress fibers induced by histamine and serotonin
Our current studies demonstrate that overexpression of TR3/Nur77 induces the formation of actin stress fibers and TR3/Nur77 anti-sense DNA inhibits the formation of actin stress fibers induced by VEGF, histamine and serotonin (Figure 1)
Summary
Pathological angiogenesis is a hallmark of many diseases including cancer, inflammation, wound healing and ischemic heart disease. It is desirable to identify additional angiogenesis targets. TR3/Nur is a member of nuclear receptor IV subfamily of transcription factors, without physiological ligand [18], several agonists, cytosporone B and a series of methylene-substituted diindolymethanes, were identified [19, 20]. The nuclear receptor IV subfamily www.impactjournals.com/oncotarget members play redundant roles in TCR-mediated apoptosis [21] and brown fat thermogenesis [22, 23]. They play different roles in development (reviewed in [24]). TR3/Nur plays important roles in cancer cell biology, inflammation, metabolism diseases, stress and addiction (reviewed in [25,26,27,28])
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