NR4A1 promotes PDGF-BB-induced cell colony formation in soft agar

PLoS One. 2014 Sep 30;9(9):e109047. doi: 10.1371/journal.pone.0109047. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agar
  • Animals
  • Becaplermin
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chemotaxis / drug effects
  • Gene Expression Regulation
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / genetics
  • MAP Kinase Kinase 2 / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NIH 3T3 Cells
  • Neuroglia / drug effects
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Nitriles / pharmacology
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-sis / pharmacology*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Sulfones / pharmacology

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Benzamides
  • NF-kappa B
  • Nitriles
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger
  • RNA, Small Interfering
  • Sulfones
  • Becaplermin
  • Agar
  • Mitogen-Activated Protein Kinase 7
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Map2k1 protein, mouse
  • Map2k2 protein, mouse

Grants and funding

This work was supported by the Ludwig Institute for Cancer Research (www.licr.org), the Swedish Research Council (K2011-67X-21859-01-6, www.vr.se) and the Swedish Cancer Society (130519, www.cancerfonden.se). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.