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Acharya, P., Engel, J.C. and Correia, M.A. (2009) Hepatic CYP3A suppression by high concentrations of proteasomal inhibitors: A consequence of endoplasmic reticulum (ER) stress induction, activation of RNA-dependent protein kinase-like ER-bound eukaryotic initiation factor 2alpha (eIF2alpha)-kinase (PERK) and general control nonderep-ressible-2 eIF2alpha kinase (GCN2), and global transla-tional shutoff. Molecular Pharmacology, 76, 503-515. doi:10.1124/mol.109.056002

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• TITLE: 26S proteasome inhibitors inhibit dexamethasone-dependent increase of tyrosine aminotransferase and tryptophan 2,3-dioxygenase mRNA levels in primary cultured rat hepatocytes

  AUTHORS: Mizuho Harashima, Masashi Hyuga, Youko Nagaoka, Chieko Saito, Minako Furukawa, Taiichiro Seki, Toyohiko Ariga, Nana Kawasaki, Shingo Niimi

  KEYWORDS: Glucocorticoid; 26S proteasome Inhibitor; Tyrosine Aminotransferase; Tryptophan 2, 3-Dioxygenase Genes

  JOURNAL NAME: Journal of Biophysical Chemistry, Vol.3 No.4, November 29, 2012

  ABSTRACT: Dexamethasone (Dex), a ligand for transcriptional enhancement of tyrosine aminotransferase (TAT) and tryptophan 2,3-dioxygenase (TO) genes, (100 nM) maximally increased these mRNA levels at 12 h and 7 h in primary cultured rat hepatocytes and the nuclear fraction, respectively. Lactacystin (5 μM) and epoxomicin (0.5 μM), 26S proteasome inhibitors, significantly suppressed the Dex-dependent maximum increase of TAT and TO mRNA levels in the cells and the nuclear fraction. Electrophoretic mobility shift assay demonstrated that lactacystin did not affect binding of glucocorticoid receptor to glucocorticoid responsive element. Furthermore, lactacystin did not affect the activation of GRE luciferase reporter by Dex transfected to the cells. The results demonstrate that 26S proteasome is positively involved in the Dex-dependent increase of TAT and TO mRNA levels in the cells and suggest that the mechanism of action of 26S proteasome may be degradation of some RNase(s), which breaks down TAT and TO mRNAs.