NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar

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.

The interaction between androgen receptor and PDGF-D in the radiation response of prostate carcinoma

“…Next we made an attempt to determine which of the PDGF D downstream signaling molecule(s) play(s) a critical role for the induction of AR expression in PCa cells. Since PDGF signaling were known to activate the MAPK and NFκB pathways , we treated PDGF D LNCaP cells with Erk (PD98065), JNK (JNK II Inhibitor) and NFκB (BAY 11‐7095) inhibitors and monitored AR levels. As shown in Figure C, the specificity of these inhibitors was confirmed by immunoblot analyses using antibodies that recognize active forms of these signaling molecules.…”

Hypoxia-induced Nur77 activates PI3K/Akt signaling via suppression of Dicer/let-7i-5p to induce epithelial-to-mesenchymal transition

“…The expression of Nur77 could be hyper-stimulated by hypoxic conditions and the dysregulation of Nur77 was shown to promote metastasis 7 . Furthermore, Nur77 could transcriptionally activate the expression of β1-integrin, β4-integrin, and Nanog, involved in cancer cell invasion and stemness 28 , 29 . This study has provided evidence that Nur77 could enhance both EMT and CSC properties of CRC cells under hypoxic condition and uncovered a novel non-genomic route for mediating these effects.…”

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

“…Nr4a1 knock down increased NIH3T3 fibroblast cell growth [90]. Overexpression of each of the Nr4a genes decreased leiomyoma smooth muscle cells, part of uterine fibroids, proliferation rate by decreasing TGFβ3, SMAD3 and collagen genes 1A1, 6A1, 6A2 and 16A1 expression [51].…”