Journal article
Development of Neh2-Luciferase Reporter and Its Application for High Throughput Screening and Real-Time Monitoring of Nrf2 Activators
Chemistry & biology, v 18(6), pp 752-765
24 Jun 2011
PMID: 21700211
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The NF-E2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant defense and detoxification. To directly monitor stabilization of Nrf2, we fused its Neh2 domain, responsible for the interaction with its nucleocytoplasmic regulator, Keap1, to firefly luciferase (Neh2-luciferase). We show that Neh2 domain is sufficient for recognition, ubiquitination, and proteasomal degradation of Neh2-luciferase fusion protein. The Neh2-luc reporter system allows direct monitoring of the adaptive response to redox stress and classification of drugs based on the time course of reporter activation. The reporter was used to screen the Spectrum library of 2000 biologically active compounds to identify activators of Nrf2. The most robust and yet nontoxic Nrf2 activators found-nordihydroguaiaretic acid, fisetin, and gedunin-induced astrocyte-dependent neuroprotection from oxidative stress via an Nrf2-dependent mechanism.
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Details
- Title
- Development of Neh2-Luciferase Reporter and Its Application for High Throughput Screening and Real-Time Monitoring of Nrf2 Activators
- Creators
- Natalya A. Smirnova - Burke Medical Research InstituteRenee E. Haskew-Layton - Burke Medical Research InstituteManuela Basso - Burke Medical Research InstituteDmitry M. Hushpulian - Lomonosov Moscow State UniversityJimmy B. Payappilly - Burke Medical Research InstituteRachel E. Speer - Cornell UniversityYoung-Hoon Ahn - Johns Hopkins UniversityIlay Rakhman - Burke Medical Research InstitutePhilip A. Cole - Johns Hopkins UniversityJohn T. Pinto - New York Medical CollegeRajiv R. Ratan - Burke Medical Research InstituteIrina G. Gazaryan - Burke Medical Research Institute
- Publication Details
- Chemistry & biology, v 18(6), pp 752-765
- Publisher
- Elsevier
- Number of pages
- 14
- Grant note
- U54RR020839 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) P01AG014930 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Thomas Hartman Foundation for Parkinsons Research R01GM062437 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Winifred Masterson Burke Relief Foundation CO19772 / Adelson Foundation for Neurorehabilitation and Repair, NYS DOH Center of Research Excellence
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Web of Science ID
- WOS:000292583800010
- Scopus ID
- 2-s2.0-79959532959
- Other Identifier
- 991020099885204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology