@article {Makia601, author = {N. L. Makia and I. Amunom and K. C. Falkner and D. J. Conklin and S. Surapureddi and J. A. Goldstein and R. A. Prough}, title = {Activator Protein-1 Regulation of Murine Aldehyde Dehydrogenase 1a1}, volume = {82}, number = {4}, pages = {601--613}, year = {2012}, doi = {10.1124/mol.112.078147}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Previously we demonstrated that aldehyde dehydrogenase (ALDH) 1a1 is the major ALDH expressed in mouse liver and is an effective catalyst in metabolism of lipid aldehydes. Quantitative real-time polymerase chain reaction analysis revealed a ≈2.5- to 3-fold induction of the hepatic ALDH1A1 mRNA in mice administered either acrolein (5 mg/kg acrolein p.o.) or butylated hydroxylanisole (BHA) (0.45\% in the diet) and of cytosolic NAD+-dependent ALDH activity. We observed ≈2-fold increases in ALDH1A1 mRNA levels in both Nrf2(+/+) and Nrf2(-/-) mice treated with BHA compared with controls, suggesting that BHA-induced expression is independent of nuclear factor E2-related factor 2 (Nrf2). The levels of activator protein-1 (AP-1) mRNA and protein, as well as the amount of phosphorylated c-Jun were significantly increased in mouse liver or Hepa1c1c7 cells treated with either BHA or acrolein. With use of luciferase reporters containing the 5'-flanking sequence of Aldh1a1 (-1963/+27), overexpression of c-Jun resulted in an ≈4-fold induction in luciferase activity, suggesting that c-Jun transactivates the Aldh1a1 promoter as a homodimer and not as a c-Jun/c-Fos heterodimer. Promoter deletion and mutagenesis analyses demonstrated that the AP-1 site at position -758 and possibly -1069 relative to the transcription start site was responsible for c-Jun-mediated transactivation. Electrophoretic mobility shift assay analysis with antibodies against c-Jun and c-Fos showed that c-Jun binds to the proximal AP-1 site at position -758 but not at -1069. Recruitment of c-Jun to this proximal AP-1 site by BHA was confirmed by chromatin immunoprecipitation analysis, indicating that recruitment of c-Jun to the mouse Aldh1a1 gene promoter results in increased transcription. This mode of regulation of an ALDH has not been described before.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/82/4/601}, eprint = {https://molpharm.aspetjournals.org/content/82/4/601.full.pdf}, journal = {Molecular Pharmacology} }