Distinct Regulations of HO-1 Gene Expression for Stress Response and Substrate Induction.

Autor: Anqi Zhang, Takafumi Suzuki, Saki Adachi, Eriko Naganuma, Norio Suzuki, Tomonori Hosoya, Ken Itoh, Sporn, Michael B., Masayuki Yamamoto
Předmět:
Zdroj: Molecular & Cellular Biology; Nov2021, Vol. 41 Issue 11, p1-22, 22p
Abstrakt: 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--DsRedknock- 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index