Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., Scrimieri, F., Winter, J. M., Hruban, R. H., Iacobuzio-Donahue, C., Kern, S. E., Blair, I. A., Tuveson, D. A. (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature, 475 (7354). pp. 106-9. ISSN 1476-4687 (Electronic)0028-0836 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/21734707
DOI: 10.1038/nature10189

Abstract

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.

Item Type: Paper
Uncontrolled Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism Alleles Animals Antioxidants/metabolism Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic/genetics/ metabolism/ pathology Cells, Cultured Cytoskeletal Proteins/genetics/metabolism Extracellular Signal-Regulated MAP Kinases/metabolism Fibroblasts/metabolism Genes, myc/genetics Humans Intracellular Signaling Peptides and Proteins/genetics/metabolism JNK Mitogen-Activated Protein Kinases/metabolism MAP Kinase Signaling System Mice Mitogen-Activated Protein Kinase Kinases/metabolism NF-E2-Related Factor 2/deficiency/genetics/ metabolism NIH 3T3 Cells Oncogenes/ genetics Oxidation-Reduction Pancreatic Neoplasms/genetics/ metabolism/ pathology Proto-Oncogene Proteins B-raf/genetics/metabolism Proto-Oncogene Proteins p21(ras)/genetics/metabolism Reactive Oxygen Species/ metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 22 Jul 2015 20:03
Last Modified: 22 Jul 2015 20:03
PMCID: PMC3404470
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31647

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