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Series GSE6451 Query DataSets for GSE6451
Status Public on Feb 22, 2007
Title A genomic screen for activators of the antioxidant response element
Organism Homo sapiens
Experiment type Expression profiling by array
Summary The antioxidant response element (ARE) is a cis-acting regulatory enhancer element found in the 5’ flanking region of many phase II detoxification enzymes. Upregulation of ARE-dependent target genes is known to have neuroprotective effects; yet, the mechanism of activation is largely unknown. By screening an arrayed collection of approximately 15,000 full-length expression cDNAs in the human neuroblastoma cell line IMR-32 with an ARE-luciferase reporter, we have identified several cDNAs not previously associated with ARE activation. A subset of cDNAs, including sequestosome 1 (SQSTM1) and dipeptidylpeptidase III (DPP3), activated the ARE in primary mouse-derived cortical neurons. Overexpression of SQSTM1 and DPP3 in IMR-32 cells stimulated NRF2 nuclear translocation and led to increased levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), a protein which is transcriptionally regulated by the ARE. When transfected into IMR-32 neuroblastoma cells that were depleted of transcription factor NRF2 by RNA interference, SQSTM1 and DPP3 were unable to activate the ARE or induce NQO1 expression, indicating that the ARE activation upon ectopic expression of these cDNAs is mediated by NRF2. Studies with pharmacological inhibitors indicated that 1-phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) signaling are also essential for activity. Lastly, overexpression of these cDNAs conferred partial resistance to hydrogen peroxide induced toxicity, consistent with the induction of antioxidant and phase II detoxification enzymes which can protect from oxidative stress. This work and other such studies may provide mechanisms for activating the ARE in the absence of general oxidative stress, and a novel therapeutic approach to degenerative diseases and aging.
Keywords: overexpression of different antioxidant response element activators
 
Overall design Samples were taken from duplicate transfections of different antioxidant response element activators
 
Contributor(s) Liu Y, Kern JT, Walker JR, Johnson JA, Schultz PG, Luesch H
Citation(s) 17360324
Submission date Dec 05, 2006
Last update date Mar 25, 2019
Contact name John R Walker
E-mail(s) jwalker@gnf.org
Phone 858-812-1636
Organization name Genomics Institute of the Novartis Research Foundation
Lab Genetics Core
Street address 10675 John Jay Hopkins
City San Diego
State/province CA
ZIP/Postal code 92121
Country USA
 
Platforms (1)
GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array
Samples (6)
GSM148453 IMR-32_pCMV_48hr_rep 1
GSM148454 IMR-32_pCMV_48hr_rep 2
GSM148455 IMR-32_pCMV-DPP3_48hr_rep 1
Relations
BioProject PRJNA98651

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE6451_RAW.tar 48.4 Mb (http)(custom) TAR (of CEL, EXP)

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