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

• Verfasst von: Behren, Andreas [VerfasserIn]
• Verfasst von: Mühlen, Sabrina [VerfasserIn]
• Verfasst von: Acuña Sanhueza, Gustavo A. [VerfasserIn]
• Verfasst von: Schwager, Christian [VerfasserIn]
• Verfasst von: Plinkert, Peter K. [VerfasserIn]
• Verfasst von: Huber, Peter E. [VerfasserIn]
• Verfasst von: Abdollahi, Amir [VerfasserIn]
• Verfasst von: Simon, Christian [VerfasserIn]
• Titel: Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras-MKK3-p38 to regulate in vitro cellular invasion
• Verf.angabe: A. Behren, S. Mühlen, G.A. Acuna Sanhueza, C. Schwager, P.K. Plinkert, P.E. Huber, A. Abdollahi and C. Simon
• Jahr: 2010
• Umfang: 12 S.
• Fussnoten: Published online 21 December 2009 ; Gesehen am 04.01.2023
• Titel Quelle: Enthalten in: Oncogene
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2010
• Band/Heft Quelle: 29(2010), 10, Seite 1519-1530
• ISSN Quelle: 1476-5594
• DOI: doi:10.1038/onc.2009.436
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Apoptosis
• Sach-SW: Cell Biology
• Sach-SW: general
• Sach-SW: Human Genetics
• Sach-SW: Internal Medicine
• Sach-SW: Medicine/Public Health
• Sach-SW: Oncology
• K10plus-PPN: 1830365509

Abstract

The Ras oncogene is known to activate three major MAPK pathways, ERK, JNK, p38 and exert distinct cellular phenotypes, that is, apoptosis and invasion through the Ras-MKK3-p38-signaling cascade. We attempted to identify the molecular targets of this pathway that selectively govern the invasive phenotype. Stable transfection of NIH3T3 fibroblasts with MKK3act cDNA construct revealed similar p38-dependent in vitro characteristics observed in Ha-RasEJ-transformed NIH3T3 cells, including enhanced invasiveness and anchorage-independent growth correlating with p38 phosphorylation status. To identify the consensus downstream targets of the Ras-MKK3-p38 cascade involved in invasion, in vitro invasion assays were used to isolate highly invasive cells from both, MKK3 and Ha-RasEJ transgenic cell lines. Subsequently a genome-wide transcriptome analysis was employed to investigate differentially regulated genes in invasive Ha-RasEJ- and MKK3act-transfected NIH3T3 fibroblasts. Using this phenotype-assisted approach combined with system level protein-interaction network analysis, we identified FOXM1, PLK1 and CDK1 to be differentially regulated in invasive Ha-RasEJ-NIH3T3 and MKK3act-NIH3T3 cells. Finally, a FOXM1 RNA-knockdown approach revealed its requirement for both invasion and anchorage-independent growth of Ha-RasEJ- and MKK3act-NIH3T3 cells. Together, we identified FOXM1 as a key downstream target of Ras and MKK3-induced cellular in vitro invasion and anchorage-independent growth signaling.