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Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras-MKK3-p38 to regulate in vitro cellular

A Behren1, S Mühlen, G A Acuna Sanhueza

  • 1Cancer Vaccine, Ludwig Institute for Cancer Research Ltd, Melbourne Centre for Clinical Sciences, Heidelberg, VIC, Australia.

Oncogene
|December 22, 2009
PubMed

Insights

The Ras oncogene pathway activates p38, promoting cell invasion. Researchers identified FOXM1 as a key target, crucial for Ras and MKK3-induced invasion and growth in NIH3T3 fibroblasts.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • The Ras oncogene activates multiple MAPK pathways, including ERK, JNK, and p38.
  • The Ras-MKK3-p38 signaling cascade mediates cellular phenotypes such as apoptosis and invasion.

Purpose of the Study:

  • To identify molecular targets of the Ras-MKK3-p38 pathway that specifically regulate cellular invasion.
  • To understand the downstream effectors governing invasive phenotypes induced by Ras activation.

Main Methods:

  • Stable transfection of NIH3T3 fibroblasts with MKK3(act) cDNA.
  • In vitro invasion assays to isolate highly invasive cells.
  • Genome-wide transcriptome analysis and protein-interaction network analysis.
  • FOXM1 RNA-knockdown experiments.

Main Results:

  • MKK3(act) transfection induced p38-dependent invasiveness and anchorage-independent growth in NIH3T3 cells.
  • Transcriptome analysis identified FOXM1, PLK1, and CDK1 as differentially regulated in invasive cells.
  • FOXM1 knockdown inhibited invasion and anchorage-independent growth in Ras- and MKK3-activated cells.

Conclusions:

  • FOXM1 is a critical downstream target of the Ras-MKK3-p38 pathway.
  • FOXM1 plays a key role in mediating Ras- and MKK3-induced cellular invasion and anchorage-independent growth.

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