Abstract
The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth.
Highlights
Platelet-derived growth factor (PDGF) is a key mitogen for cells of mesenchymal origin, with important functions during embryonic development and wound healing
Previous studies have implicated MAP-kinases in the regulation of NR4A1 expression [25] [40] [41], and we originally identified NR4A1 as a gene requiring Erk5 for its expression in response to platelet-derived growth factor -BB (PDGF-BB) stimulation in a microarray analysis comparing Erk52/2 mouse embryonic fibroblasts transduced with empty virus or reconstituted with Erk5 [42]
We found that PDGF-BB stimulation of NIH3T3 cells resulted in a robust upregulation of NR4A1 mRNA and protein
Summary
Platelet-derived growth factor (PDGF) is a key mitogen for cells of mesenchymal origin, with important functions during embryonic development and wound healing. The biologically active isoforms of PDGF are disulfide-bonded dimers of A, B, C or D polypeptide chains, i.e. PDGF-AA, -BB, -AB, -CC and -DD, which bind to structurally related a- and b-tyrosine kinase receptors (PDGFRa and PDGFRb, respectively). Examples include GRB2/SOS1 which activates extracellular signal-regulated kinase 1 and 2 (Erk1/2) MAP kinase, phosphatidylinositol 3-kinase (PI3-kinase), phospholipase C-c, STAT family members, members of the Src family of tyrosine kinases, and the protein tyrosine phosphatase SHP-2 [1] [2]. These signaling pathways promote cell proliferation, migration and survival. Overactivity of PDGF pathways is implicated in diseases involving excessive cell growth, including malignancies, cardiovascular disease and fibrosis [3]
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