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

被引：23

作者：

Zhang, Anqi ^{[1
]}

Suzuki, Takafumi ^{[1
]}

Adachi, Saki ^{[1
]}

Naganuma, Eriko ^{[1
]}

Suzuki, Norio ^{[2
,3
]}

Hosoya, Tomonori ^{[4
]}

Itoh, Ken ^{[4
]}

Sporn, Michael B. ^{[5
]}

Yamamoto, Masayuki ^{[1
,6
,7
]}

机构：

[1] Tohoku Univ, Grad Sch Med, Dept Med Biochem, Sendai, Miyagi, Japan

[2] Tohoku Univ, Grad Sch Med, United Ctr Adv Res, Div Oxygen Biol, Sendai, Miyagi, Japan

[3] Tohoku Univ, Grad Sch Med, United Ctr Translat Med, Div Oxygen Biol, Sendai, Miyagi, Japan

[4] Hirosaki Univ, Grad Sch Med, Dept Stress Response Sci, Hirosaki, Aomori, Japan

[5] Dartmouth Med Sch, Mol & Syst Biol, Lebanon, NH USA

[6] Tohoku Med Megabank Org, Sendai, Miyagi, Japan

[7] Tohoku Univ, Adv Res Ctr Innovat Next Generat Med INGEM, Sendai, Miyagi, Japan

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2021年 / 41卷 / 11期

关键词：

HO-1; NRF2; stress response; hemin; HEME OXYGENASE-1 GENE; COBALT CHLORIDE; TRANSCRIPTION FACTORS; CDDO-IMIDAZOLIDE; POTENT INDUCERS; BINDING-SITES; SPI-C; NRF2; MACROPHAGES; ACTIVATION;

D O I：

10.1128/MCB.00236-21

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-7 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-7 gene is floxed by loxP sites and the DsRed gene has been inserted. Myeloid lineage-specific recombination of the foxed 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.

引用

页数：22

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