PMID:19696738

Citation	Park, HJ, Carr, JR, Wang, Z, Nogueira, V, Hay, N, Tyner, AL, Lau, LF, Costa, RH and Raychaudhuri, P (2009) FoxM1, a critical regulator of oxidative stress during oncogenesis. EMBO J. 28:2908-18
Abstract	The transcription factor FoxM1 is over-expressed in most human malignancies. Although it is evident that FoxM1 has critical functions in tumour development and progression, the mechanisms by which FoxM1 participates in those processes are not understood. Here, we describe an essential role of FoxM1 in the regulation of oxidative stress that contributes to malignant transformation and tumour cell survival. We identify a negative feedback loop involving FoxM1 that regulates reactive oxygen species (ROS) in proliferating cells. We show that induction of FoxM1 by oncogenic Ras requires ROS. Elevated FoxM1, in turn, downregulates ROS levels by stimulating expression of ROS scavenger genes, such as MnSOD, catalase and PRDX3. FoxM1 depletion sensitizes cells to oxidative stress and increases oncogene-induced premature senescence. Moreover, tumour cells expressing activated AKT1 are 'addicted' to FoxM1, as they require continuous presence of FoxM1 for survival. Together, our results identify FoxM1 as a key regulator of ROS in dividing cells, and provide insights into the mechanism how tumour cells use FoxM1 to control oxidative stress to escape premature senescence and apoptosis.
Links	PubMed PMC2760115 Online version:10.1038/emboj.2009.239
Keywords	Animals; Cell Line, Tumor; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; Osteosarcoma/metabolism; Oxidative Stress; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/metabolism; Reactive Oxygen Species/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:Q922T7	involved_in	GO:0000302: response to reactive oxygen species	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:Q922T7	involved_in	GO:0032873: negative regulation of stress-activated MAPK cascade	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXO1	involved_in	GO:0032873: negative regulation of stress-activated MAPK cascade	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXM1	involved_in	GO:0090344: negative regulation of cell aging	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXM1	involved_in	GO:0008284: positive regulation of cell population proliferation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXM1	involved_in	GO:0032873: negative regulation of stress-activated MAPK cascade	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXM1	involved_in	GO:0046578: regulation of Ras protein signal transduction	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXM1	involved_in	GO:0071156: regulation of cell cycle arrest	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXM1	involved_in	GO:2000377: regulation of reactive oxygen species metabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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