Preferential expression of antioxidant response element mediated gene expression in astrocytes.
Transcriptional control of target genes by antioxidant/electrophile response elements has been well described in peripheral tissues. Genes that are regulated by this mechanism include the antioxidant enzymes NAD(P)H:quinone oxidoreductase, gamma-glutamyl cystine synthetase and glutathione-S-transferase. Antioxidant/electrophile response elements within a gene's promoter confer induction by low-molecular-weight electrophilic compounds such as tert-butylhydroquinone and dimethyl fumarate. We have now examined the ability of antioxidant/electrophile response elements to elicit gene expression in neurons and astrocytes in both brain slices and primary cultures using transient transfection of promoter reporter constructs. Our results using a heat-stable human placental alkaline phosphatase reporter indicate that antioxidant/electrophile response element mediated gene expression is largely restricted to astrocyte cell populations. Placental alkaline phosphatase expression was significantly elevated in astrocytes treated with the antioxidant/electrophile response element inducer dimethyl fumarate. Mutant constructs lacking a functional antioxidant/electrophile response element abolished all placental alkaline phosphatase expression in astrocytes. We suggest that astrocytic metabolic processes that normally aid and/or protect neurons may be controlled via this inducible system.
Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada. thmurphy@interchange.ubc.ca
T H
TH
Murphy
J
J
Yu
R
R
Ng
D A
DA
Johnson
H
H
Shen
C R
CR
Honey
J A
JA
Johnson
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D019470:Biolistics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D005910:Glioma; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D006825:Hybridomas; D006873:Hydroquinones / Q000494:pharmacology; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009447:Neuroblastoma; D009457:Neuroglia / Q000166:cytology / Q000502:physiology; D011401:Promoter Regions, Genetic; D011808:Quinone Reductases / Q000235:genetics*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection
D000975:Antioxidants; D005650:Fumarates; D006873:Hydroquinones; D011993:Recombinant Fusion Proteins; C018855:2-tert-butylhydroquinone; D011808:Quinone Reductases; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; D000069462:Dimethyl Fumarate