Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis.

Nature | Jul 6, 2011

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.

Pubmed ID: 21734707 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Alleles | Animals | Antioxidants | Cell Line, Tumor | Cell Proliferation | Cell Transformation, Neoplastic | Cells, Cultured | Cytoskeletal Proteins | Extracellular Signal-Regulated MAP Kinases | Fibroblasts | Genes, myc | Humans | Intracellular Signaling Peptides and Proteins | JNK Mitogen-Activated Protein Kinases | Kelch-Like ECH-Associated Protein 1 | MAP Kinase Signaling System | Mice | Mitogen-Activated Protein Kinase Kinases | NF-E2-Related Factor 2 | NIH 3T3 Cells | Oncogenes | Oxidation-Reduction | Pancreatic Neoplasms | Proto-Oncogene Proteins B-raf | Proto-Oncogene Proteins p21(ras) | Reactive Oxygen Species

Research tools detected in this publication

Data used in this publication

None found

Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA128920
  • Agency: NCI NIH HHS, Id: U01 CA111294
  • Agency: NCI NIH HHS, Id: P50 CA062924
  • Agency: NCI NIH HHS, Id: CA62924
  • Agency: NCI NIH HHS, Id: F32 CA123887
  • Agency: NCI NIH HHS, Id: CA106610
  • Agency: NCI NIH HHS, Id: U01 CA084291
  • Agency: NCI NIH HHS, Id: CA084291
  • Agency: NCI NIH HHS, Id: CA101973
  • Agency: NCI NIH HHS, Id: K08 CA106610
  • Agency: Cancer Research UK, Id: U01 CA105490
  • Agency: NCI NIH HHS, Id: CA128920
  • Agency: NCI NIH HHS, Id: R01 CA101973-05
  • Agency: NCI NIH HHS, Id: CA105490
  • Agency: NCI NIH HHS, Id: R01 CA101973
  • Agency: NCI NIH HHS, Id: CA111294
  • Agency: NCI NIH HHS, Id:

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


Primer3

Tool used to design PCR primers from DNA sequence - often in high-throughput genomics applications. It does everything from mispriming libraries to sequence quality data to the generation of internal oligos.

tool

View all literature mentions

ENCODE - Encyclopedia of DNA Elements

Encyclopedia of DNA elements consisting of a comprehensive parts list of functional elements in the human genome, including elements that act at the protein and RNA levels, and regulatory elements that control cells and circumstances in which a gene is active, that is freely available as as a fundamental information resource for all biomedical researchers. ENCODE enables the scientific and medical communities to interpret the role of the human genome in biology and disease. ENCODE provides identification of common cell types to facilitate integrative analysis and a new experimental technologies based on high-throughput sequencing. ENCODE data are available for the entire human genome. All ENCODE data are free and available for immediate use.

tool

View all literature mentions

Sequencher

Software for Next-Generation DNA sequencing, Sanger DNA analysis, and RNA sequencing. It contains sequence analysis tools which include reference-guided alignments, de novo assembly, variant calling, and SNP analyses. It has integrated the Cufflinks suite for in-depth transcript analysis and differential gene expression of RNA-Seq data.

tool

View all literature mentions

Symansis

An Antibody supplier

tool

View all literature mentions