ArticleOncogene2003
Nrf2 is an inhibitor of the Fas pathway as identified by Achilles' Heel Method, a new function-based approach to gene identification in human cells.
Article in Oncogene, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 76 citations in OpenAlex.
- Hederagenin Suppresses Inflammation and Cartilage Degradation to Ameliorate the Progression of Osteoarthritis: An In vivo and In vitro Study.Inflammation · 2023Article
- Involvement of redox signalling in tumour cell dormancy and metastasis.Cancer metastasis reviews · 2023Review
- Junction of the redox dynamic, orchestra of signaling, and altered metabolism in regulation of T- cell lymphoma.Frontiers in oncology · 2023Review
- Ascorbyl stearate stimulates cell death by oxidative stress-mediated apoptosis and autophagy in HeLa cervical cancer cell line in vitro.3 Biotech · 2019Article
- NRF2 and the Hallmarks of Cancer.Cancer cell · 2018Review
- Nrf2/ARE pathway attenuates oxidative and apoptotic response in human osteoarthritis chondrocytes by activating ERK1/2/ELK1-P70S6K-P90RSK signaling axis.Free radical biology & medicine · 2018Article
- Reactive Oxygen Species: A Key Constituent in Cancer Survival.Biomarker insights · 2018Review
- Immunohistochemical Study of Nrf2-Antioxidant Response Element as Indicator of Oxidative Stress Induced by Cadmium in Developing Rats.Oxidative medicine and cellular longevity · 2015Article
- Silencing of Hsp90 chaperone expression protects against 6-hydroxydopamine toxicity in PC12 cells.Journal of molecular neuroscience : MN · 2014Article
- Over-expression of Nrf2 diminishes ethanol-induced oxidative stress and apoptosis in neural crest cells by inducing an antioxidant response.Reproductive toxicology (Elmsford, N.Y.) · 2013Article
- Sulforaphane protects against ethanol-induced oxidative stress and apoptosis in neural crest cells by the induction of Nrf2-mediated antioxidant response.British journal of pharmacology · 2013Article
- Activation of the nuclear factor E2-related factor 2/antioxidant response element pathway is neuroprotective after spinal cord injury.Journal of neurotrauma · 2012Article
- Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS.Neurology research international · 2012Article
- Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters.International journal of molecular sciences · 2012Article
- The pesticide deltamethrin increases free radical production and promotes nuclear translocation of the stress response transcription factor Nrf2 in rat brain.Toxicology and industrial health · 2011Article
- Stabilization of Nrf2 protein by D3T provides protection against ethanol-induced apoptosis in PC12 cells.PloS one · 2011Article
- Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance.Antioxidants & redox signaling · 2010Article
- Induction of the Nrf2-driven antioxidant response by tert-butylhydroquinone prevents ethanol-induced apoptosis in cranial neural crest cells.Biochemical pharmacology · 2010Article
- 3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington's disease: past, present and future.Molecules (Basel, Switzerland) · 2010Review
- Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth.Molecular cancer therapeutics · 2010Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Here we describe the Achilles' Heel Method (AHM), a new function-based approach for identification of inhibitors of signaling pathways, optimized for human cells. The principle of AHM is the identification of 'sensitizing' cDNAs based on their decreased abundance following selection. As a proof of principle, we have employed AHM for the identification of Fas/CD95/APO-1 pathway inhibitors. HeLa cells were transfected with an antisense cDNA expression library in an episomal vector followed by selection with a suboptimal dose of the apoptotic inducer. Antisense inactivation of Fas inhibitors rendered the cells more sensitive to apoptosis resulting in their preferential death and consequent loss of their sensitizing episomes that were identified by subtraction. We show that the resulting products were enriched for sensitizing cDNAs as seven out of eight candidates tested were confirmed as inhibitors of Fas-induced killing either by transfection or by pharmacological inhibition. Furthermore, we demonstrate by multiple approaches that one candidate, NF-E2 related factor 2 (Nrf2), is an inhibitor of Fas-induced apoptosis. Inactivation of Nrf2 by antisense or by a membrane permeable dominant-negative polypeptide sensitized cells while overexpression of Nrf2 protected cells from Fas-induced apoptosis. In addition, dicumarol, an inhibitor of the phase II detoxifying enzyme NQO1, a downstream target of Nrf2, sensitized cells. Nrf2 induces the production of Glutathione (GSH) and we demonstrated that N-acetyl L-cysteine (NAC), a precursor to GSH, protected cells from Fas-mediated killing. Taken together, AHM is a powerful approach for the identification of inhibitors of a signaling pathway with a low rate of false positives that opens new avenues for function profiling of human genes and discovery of new drug targets.
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