| First Author | Nakano N | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 27 | Pages | 9033-9051 |
| PubMed ID | 32409577 | Mgi Jnum | J:297156 |
| Mgi Id | MGI:6466934 | Doi | 10.1074/jbc.RA120.013596 |
| Citation | Nakano N, et al. (2020) Dissociation of the AhR/ARNT complex by TGF-beta/Smad signaling represses CYP1A1 gene expression and inhibits benze[a]pyrene-mediated cytotoxicity. J Biol Chem 295(27):9033-9051 |
| abstractText | Cytochrome P450 1A1 (CYP1A1) catalyzes the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) and is transcriptionally regulated by the aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) complex upon exposure to PAHs. Accordingly, inhibition of CYP1A1 expression reduces production of carcinogens from PAHs. Although transcription of the CYP1A1 gene is known to be repressed by transforming growth factor-beta (TGF-beta), how TGF-beta signaling is involved in the suppression of CYP1A1 gene expression has yet to be clarified. In this study, using mammalian cell lines, along with shRNA-mediated gene silencing, CRISPR/Cas9-based genome editing, and reporter gene and quantitative RT-PCR assays, we found that TGF-beta signaling dissociates the B[a]P-mediated AhR/ARNT heteromeric complex. Among the examined Smads, Smad family member 3 (Smad3) strongly interacted with both AhR and ARNT via its MH2 domain. Moreover, hypoxia-inducible factor 1alpha (HIF-1alpha), which is stabilized upon TGF-beta stimulation, also inhibited AhR/ARNT complex formation in the presence of B[a]P. Thus, TGF-beta signaling negatively regulated the transcription of the CYP1A1 gene in at least two different ways. Of note, TGF-beta abrogated DNA damage in B[a]P-exposed cells. We therefore conclude that TGF-beta may protect cells against carcinogenesis because it inhibits CYP1A1-mediated metabolic activation of PAHs as part of its anti-tumorigenic activities. |
