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.
Highlights
Glucocorticoids stimulate transcription of target genes [1], including tyrosine aminotransferase (TAT) [2,3] and tryptophan 2,3-dioxygenase (TO) [4,5], by activating glucocorticoid receptor (GR)
There is one report showing that proteasome inhibitors block the degradation of RNase L caused by phorbor12-myristate-13-acetae in mouse L929 cells, suggesting that degradation of target mRNA may be stimulated by proteasome inhibitors [23]
These findings indicate that inhibition of Dex-dependent increase of TAT and TO mRNA levels was common to 26S proteasome inhibitors, but not specific to a certain 26S proteasome inhibitor
Summary
Glucocorticoids stimulate transcription of target genes [1], including tyrosine aminotransferase (TAT) [2,3] and tryptophan 2,3-dioxygenase (TO) [4,5], by activating glucocorticoid receptor (GR). Activation of GR by glucocorticoids is a multiple-step process that involves the ability of GR to recognize and bind to glucocorticoids, to undergo glucocorticoid-dependent structural transformation, and to translocate into the nucleus, where it binds to specific DNA sequences, glucocorticoid response elements, which are associated with target genes [6,7]. TAT and TO are the main enzymes involved in gluconeogenesis in rat liver in vivo [24,25,26]. Primary cultured rat hepatocytes are a suitable model system for investigation of the physiological functions of 26S proteasome in rat liver in vivo [27,28,29,30,31]
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