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Antioxid Redox Signal. 2014 Dec 20;21(18):2498-514. doi: 10.1089/ars.2014.5843. Epub 2014 Jul 31.

The PTEN/NRF2 axis promotes human carcinogenesis.

Author information

1
1 Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , and Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Madrid, Spain .

Abstract

AIMS:

A recent study conducted in mice reported that liver-specific knockout of tumor suppressor Pten augments nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional activity. Here, we further investigated how phosphatase and tensin homolog deleted on chromosome 10 (PTEN) controls NRF2 and the relevance of this pathway in human carcin ogenesis.

RESULTS:

Drug and genetic targeting to PTEN and phosphoproteomics approaches indicated that PTEN leads to glycogen synthase kinase-3 (GSK-3)-mediated phosphorylation of NRF2 at residues Ser(335) and Ser(338) and subsequent beta-transducin repeat containing protein (β-TrCP)-dependent but Kelch-like ECH-associated protein 1 (KEAP1)-independent degradation. Rescue experiments in PTEN-deficient cells and xerographs in athymic mice indicated that loss of PTEN leads to increased NRF2 signature which provides a proliferating and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1).

INNOVATION:

These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3/β-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas.

CONCLUSION:

Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target.

PMID:
24892215
PMCID:
PMC4245871
DOI:
10.1089/ars.2014.5843
[Indexed for MEDLINE]
Free PMC Article
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