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Distinct Regulations of HO-1 Gene Expression for Stress Response and Substrate Induction.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2021 Oct 26; Vol. 41 (11), pp. e0023621. Date of Electronic Publication: 2021 Aug 16. - Publication Year :
- 2021
-
Abstract
- Heme oxygenase 1 (HO-1) is the key enzyme for heme catabolism and cytoprotection. Whereas HO-1 gene expression in response to various stresses has been investigated extensively, the precise mechanisms by which HO-1 gene expression is regulated by the HO-1 substrate heme remain elusive. To systematically examine whether stress-mediated induction and substrate-mediated induction of HO-1 utilize similar or distinct regulatory pathways, we developed an HO-1-DsRed-knock-in reporter mouse in which the HO-1 gene is floxed by loxP sites and the DsRed gene has been inserted. Myeloid lineage-specific recombination of the floxed locus led to fluorescence derived from expression of the HO-1-DsRed fusion protein in peritoneal macrophages. We also challenged general recombination of the locus and generated mice harboring heterozygous recombinant alleles, which enabled us to monitor HO-1-DsRed expression in the whole body in vivo and ex vivo . HO-1 inducers upregulated HO-1-DsRed expression in myeloid lineage cells isolated from the mice. Notably, analyses of peritoneal macrophages from HO-1-DsRed mice lacking NRF2, a major regulator of the oxidative/electrophilic stress response, led us to identify NRF2-dependent stress response-mediated HO-1 induction and NRF2-independent substrate-mediated HO-1 induction. Thus, the HO-1 gene is subjected to at least two distinct levels of regulation, and the available lines of evidence suggest that substrate induction in peritoneal macrophages is independent of CNC family-based regulation.
- Subjects :
- Animals
Antioxidants metabolism
Bilirubin metabolism
Biliverdine metabolism
Heme Oxygenase-1 biosynthesis
Luminescent Proteins genetics
Membrane Proteins biosynthesis
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-E2-Related Factor 2 genetics
Oxidative Stress physiology
Gene Expression Regulation genetics
Heme metabolism
Heme Oxygenase-1 genetics
Macrophages, Peritoneal metabolism
Membrane Proteins genetics
Oxidative Stress genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 41
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 34398680
- Full Text :
- https://doi.org/10.1128/MCB.00236-21